Fused phenyl amido heterocyclic compounds

ABSTRACT

The present invention relates to a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
     Ring A is (4-12)-membered heterocyclyl; 
     Ring B is a fused benzene ring selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     Ring A, ring B, ring C, R 1 , R 1a , R 2 , R 3 , R 4 , L 2 , n, t, w, and z are as defined in the specification. The invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and methods of treating a condition that is mediated by the modulation of glucokinase, the method comprising administering to a mammal an effective amount of a compound of formula (I).

This application is a continuation filing of U.S. patent application Ser. No. 11/746,359 filed May 9, 2007, which claims the benefit of International Application No. PCT/IB2007/001035 filed Apr. 11, 2007, which claims the benefit of Provisional Patent Application No. 60/793,703 filed Apr. 20, 2006.

FIELD OF THE INVENTION

The present invention relates to novel fused phenyl amido heterocyclic compounds of formula (I), to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in the preparation of a medicament for use in the treatment or prevention of a disease or medical condition mediated through glucokinase (GK), leading to a decreased glucose threshold for insulin secretion. In addition the compounds are predicted to lower blood glucose by increasing hepatic glucose uptake. Such compounds may have utility in the treatment of Type 2 diabetes and obesity.

BACKGROUND OF THE INVENTION

In the pancreatic beta cell and liver parenchymal cells the main plasma membrane glucose transporter is GLUT2. Under physiological glucose concentrations the rate at which GLUT2 transports glucose across the membrane is not rate limiting to the overall rate of glucose uptake in these cells. The rate of glucose uptake is limited by the rate of phosphorylation of glucose to glucose-6-phosphate (G-6-P) which is catalysed by glucokinase (GK). GK has a high (6-10 mM) Km for glucose and is not inhibited by physiological concentrations of G-6-P. GK expression is limited to a few tissues and cell types, most notably pancreatic beta cells and liver cells (hepatocytes). In these cells GK activity is rate limiting for glucose utilization and therefore regulates the extent of glucose induced insulin secretion and hepatic glycogen synthesis. These processes are critical in the maintenance of whole body glucose homeostasis and both are dysfunctional in diabetes.

The compounds of the present invention are GK agonists, and are therefore believed to be useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, hypertension, and metabolic diseases.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Ring A is (4-12)-membered heterocyclyl;

Ring B is a fused benzene ring selected from the group consisting of:

wherein in each of the above formula B(i) and B(ii), bond a is connecting said ring B fused benzene ring to the group -L²-R² and bond b is connecting said ring B fused benzene ring to the group >C═O—NH—;

Each R¹ and R⁴can be independently bonded to any carbon atom or nitrogen atom of ring C;

Ring C contains an optional double bond and an optional heteroatom selected from the group consisting of —O—, —NR⁵—, and —S—;

each of R¹, R^(1a), and R⁴ are independently selected from H, halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁵, —(C═O)—O—R⁵, —O—C═O)—R⁵, —NR⁵(C═O)—R⁷, —(C═O)—NR⁵R⁶, —NR⁵R⁶, —NR⁵OR⁶, —S(O)_(k)NR⁵R⁶, —S(O)₁(C₁-C₆)alkyl, —O—SO₂—R⁵, —NR⁵—S(O)_(k), —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), —(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, and —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl; or

R¹ and R⁴, if they are both attached on one carbon atom of the ring C, together optionally form a (3-10)-membered cycloalkyl or (4-12)-membered heterocyclyl ring;

L² is >C═O, >C═O—O—, —O—C═O—, —O—C═O—O—, —O—C═O—NR⁵—, —NR⁵—(C═O)—, —NR⁵—(C═O)—O—, —NR⁵—(C═O)—NR⁶, —(C═O)—NR⁵—, —O—, —NR⁵—, —S(O)_(j)—, —NR⁵SO₂—, —SO₂NR⁵—, —(C═O)NR⁵SO₂—, —SO₂NR⁵(C═O)—, or —CR⁵R⁶;

R² is H, (C₁-C₆)alkyl, —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), or —(CR⁵R⁶)_(v)(4-12)-membered heterocyclyl;

R³ is H, halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁵, —(C═O)—O—R⁵, —O—(C═O)—R⁵, —NR⁵(C═O)—R⁷, —(C═O)—NR⁵R⁶, —NR⁵R⁶, —NR⁵OR⁶, —S(O)_(k)NR⁵R⁶, —S(O)_(j)(C₁-C₆)alkyl, —O—SO₂—R⁵, —NR⁵—S(O)_(k), —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), —(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, or —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl;

each of R⁵, R⁶ and R⁷ are independently selected from H, (C₁-C₆)alkyl, —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(p)(C₆-C₁₀)aryl, and —(CR⁸R⁹)_(p)(4-10)-membered heterocyclyl;

any carbon atoms of the (C₁-C₆)alkyl, the (3-10)-membered cycloalkyl, the (C₆-C₁₀)aryl and the (4-10)-membered heterocyclyl of the foregoing R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently optionally substituted with 1 to 3 R¹¹ substituents each independently selected from halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, —O—R¹², (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—R¹², —(C═O)—O—R⁸, —(C═O)—O—R¹², —O—(C═O)—R⁸, —O—(C═O)—R¹², —NR⁸(C═O)—R¹⁰, —(C═O)—NR⁸R⁹, —(C═O)—NR⁸R¹², —NR⁸R⁹, —NR⁸R¹², —NR⁸OR⁹, —NR⁸OR¹², —S(O)_(k)NR⁸R⁹, —S(O)_(k)NR⁸R¹², —S(O)_(j)(C₁-C₆)alkyl, —S(O)_(j)R¹², —O—SO₂—R⁸, —O—SO₂—R¹², —NR⁸—S(O)_(k), —NR¹²—S(O)_(k), —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(C₆-C₁₀)aryl, —(CR⁸ R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(v)O(CR⁸ R⁹)_(q)(C₆-C₁₀)aryl, —(CR⁸R⁹)_(v)O(CR⁸R⁹)_(q)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(q)S(O)_(j)(CR⁸R⁹)_(v)(C₆-C₁₀)aryl, and —(CR⁸R⁹)_(q)S(O)_(j)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl;

any carbon atoms of the (C₁-C₆)alkyl, the (3-10)-membered cycloalkyl, the (C₆-C₁₀)aryl and the (4-10)-membered heterocyclyl of the foregoing R¹¹ are independently optionally substituted with 1 to 3 R¹³ substituents each independently selected from halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, (CH₂)_(v)OH, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—R¹², —(C═O)—O—R⁸, —(C═O)—O—R¹², —O—(C═O)—R⁸, —O—(C═O)—R¹², —NR⁸(C═O)—R¹⁰, —(C═O)—NR⁸R⁹, —NR⁸R⁹, and —NR⁸R¹²;

any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹ and R¹² are independently optionally substituted with (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—O—R⁸, —(C═O)—NR⁸R⁹, —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(C₆-C₁₀)aryl, or —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl;

each R⁸, R⁹, and R¹⁰ are independently H or (C₁-C₆)alkyl;

R¹² is —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), or —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl;

p, q, and v are each independently 0, 1, 2, 3, 4, or 5;

w, n and j are each independently 0, 1, or 2;

k is 1 or 2; and

t and z are each independently 1, 2, 3, or 4;

with the proviso that when compound (I) has the formula:

Wherein:

Ring A is pyridin-2-yl or thiazol-2-yl;

L² is —O—; and

R² is (C₁-C₆)alkyl, —(CR⁸R⁸)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁸)_(v)(C₆-C₁₀aryl), or —(CR⁸R⁸)_(v)(4-12)-membered heterocyclyl; then

R² is further substituted by R¹¹ substituents each independently selected from —SO₂—(C₁-C₆)alkyl, —S(O)_(j)R¹², —S(O)_(k)NR⁸R⁹, —S(O)_(k)NR⁸R¹², —(C═O)—R¹², —(C═O)—NR⁸R⁹, and —(C═O)—NR⁸R¹².

The present invention also relates to said compound of formula (I) selected from the group consisting of:

wherein said L², R¹, R^(1a), R², R³, ring A, t, z, w, and n are as defined above; and

-   wherein ring C is (4-6)-membered heterocyclyl or a (4-10)-membered     cycloalkyl.

The present invention also relates to said compound of formula (I) selected from the group consisting of compounds of formula (II) (III), (IV), or (V):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Ring A is (4-12)-membered heterocyclyl;

L¹ is —O—, —NR⁵—, —S—, or —CR⁵R⁶—;

each of R¹, R^(1a), and R⁴ are independently selected from H, halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁵, —(C═O)—O—R⁵, —O—(C═O)—R⁵, —NR⁵(C═O)—R⁷, —(C═O)—NR⁵R⁶, —NR⁵R⁶, —NR⁵OR⁶, —S(O)_(k)NR⁵R⁶, —S(O)_(j)(C₁-C₆)alkyl, —O—SO₂—R⁵, —NR⁵—S(O)_(k), —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), —(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, and —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl; or

R¹ and R⁴, if they are both attached on one carbon atom of the ring containing L¹, together optionally form a (3-10)-membered cycloalkyl or (4-10)-membered heterocyclyl ring;

The ring containing L¹ contains an optional double bond;

L² is >C═O, >C═O—O—, O—C═O—, —O—C═O—O—, —O—C═O—NR⁵—, —NR⁵—(C═O)—, —NR⁵—(C═O)—O—, —NR⁵—(C═O)—NR⁶, —(C═O)—NR⁵—, —O—, —NR⁵—, —S(O)_(j)—, —NR⁵SO₂—, —SO₂NR⁵—, —(C═O)NR⁵SO₂—, —SO₂NR⁵(C═O)—, or —CR⁵R⁶;

R² is H, (C₁-C₆)alkyl, —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), or —(CR⁵R⁶)_(v)(4-12)-membered heterocyclyl;

R³ is H, halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁵, —(C═O)—O—R⁵, —O—(C═O)—R⁵, —NR⁵(C═O)—R⁷, —(C═O)—NR⁵R⁶, —NR⁵R⁶, —NR⁵OR⁶, —S(O)_(k)NR⁵R⁶, —S(O)_(j)(C₁-C₆)alkyl, —O—SO₂—R⁵, —NR⁵—S(O)_(k), —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), —(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, or —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl;

each of R⁵, R⁶ and R⁷ are independently selected from H, (C₁-C₆)alkyl, —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(p)(C₆-C₁₀)aryl, and —(CR⁸R⁹)_(p)(4-10)-membered heterocyclyl;

any carbon atoms of the (C₁-C₆)alkyl, the (3-10)-membered cycloalkyl, the (C₆-C₁₀)aryl and the (4-10)-membered heterocyclyl of the foregoing R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently optionally substituted with 1 to 3 R¹¹ substituents each independently selected from halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, —O—R¹², (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—R¹², —(C═O)—O—R⁸, —(C═O)—O—R¹², —O—(C═O)—R⁸, —O—(C═O)—R¹², —NR⁸(C═O)—R¹⁰, —(C═O)—NR⁸R⁹, —(C═O)—NR⁸R¹², —NR⁸R⁹, —NR⁸R¹², —NR⁸OR⁹, —NR⁸OR¹², —S(O)_(k)NR⁸R⁹, —S(O)_(k)NR⁸R¹², —S(O)_(j)(C₁-C₆)alkyl, —S(O)_(j)R¹², —O—SO₂—R⁸, —O—SO₂—R¹², —NR⁸—S(O)_(k), —NR¹²—S(O)_(k), —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(C₆-C₁₀)aryl, —(CR⁸R⁹)_(q)(C═O)_(q)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(v)O(CR⁸R⁹)_(q)(C₆-C₁₀)aryl, —(CR⁸R⁹)_(v)O(CR⁸R⁹)_(q)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(q)S(O)_(j)(CR⁸R⁹)_(v)(C₆-C₁₀)aryl, and —(CR⁸R⁹)_(q)S(O)_(j)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl;

any carbon atoms of the (C₁-C₆)alkyl, the (3-10)-membered cycloalkyl, the (C₆-C₁₀)aryl and the (4-10)-membered heterocyclyl of the foregoing R¹¹ are independently optionally substituted with 1 to 3 R¹³ substituents each independently selected from halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, (CH₂)_(v)OH, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—R¹², —(C═O)—O—R⁸, —(C═O)—O—R¹², —O—(C═O)—R⁸, —O—(C═O)—R¹², —NR⁸(C═O)—R¹⁰, —(C═O)—NR⁸R⁹, —(C═O)—NR⁸R¹², —NR⁸R⁹, and —NR⁸R¹²;

any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹ and R¹² are independently optionally substituted with (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—O—R⁸, —(C═O)—NR⁸R⁹, —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(C₆-C₁₀)aryl, or —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl;

each R⁸, R⁹, and R¹⁰ are independently H or (C₁-C₆)alkyl;

R¹² is —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), or —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl;

p, q, and v are each independently 0, 1, 2, 3, 4, or 5;

m is 0, 1, 2, or 3;

w, n and j are each independently 0, 1, or 2;

k is 1 or 2; and

t and z are each independently 1, 2, 3, or 4.

Preferably t is 1 or 2.

Preferably z is 1 or 2.

In another embodiment, the invention relates to compounds of the formula (II) selected from the group consisting of

wherein said L¹, L², R¹, R^(1a), R², R³, R⁴, ring A, w, and n are as defined above.

In another embodiment, the invention relates to compounds of the formula (III) selected from the group consisting of:

wherein said L¹, L², R¹, R^(1a), R², R³, R⁴, ring A, w, and n are as defined above.

In another embodiment, the invention relates to compounds of the formula (IV) selected from the group consisting of:

wherein said L¹, L², R¹, R^(1a), R², R³, R⁴, ring A, w, and n are as defined above.

In another embodiment, the invention relates to compounds of the formula (V) selected from the group consisting of:

wherein said L¹, L², R¹, R^(1a), R², R³, R⁴, ring A, w, and n are as defined above.

In a preferred embodiment, the invention relates to compounds of the formula (II), wherein said compound of formula (II) has the structure of formula (IIa) as described above.

In another preferred embodiment, the invention relates to compounds of the formula (IV), wherein said compound of formula (IV) has the structure of formula (IVa) as described above.

In another embodiment, the invention relates to compounds of the formula (I) wherein said Ring A is selected from the group consisting of oxadiazolyl, triazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, pyridinylcyclohexyl, and naphthyridinyl.

In another embodiment, the invention relates to compounds of the formula (I) wherein said Ring A is a 5-membered heterocyclyl selected from the group consisting of oxadiazolyl, triazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, isoxazolyl, isothiazolyl, and thiadiazolyl. Preferably, Ring A is pyrazolyl, pyrazolinyl, isoxazolyl, and triazolyl.

In another embodiment, the invention relates to compounds of the formula (I) wherein said Ring A is a 6-membered heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl. Preferably, Ring A is pyridinyl, pyrimidinyl, and pyrazinyl.

In another embodiment, the invention relates to compounds of the formula (I) wherein said Ring A is a 9-membered or 10-membered heterocyclyl selected from the group consisting of benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, pyridinylcyclohexyl, and naphthyridinyl.

In another embodiment, the invention relates to compounds of the formula (I) selected from the group consisting of (VIa), (VIb), (VIc) and (VId):

wherein

L², R¹, R², R³, R⁴, ring A, w, and n are as defined above;

L¹ is —O—, —NR⁵—, or —S—;

with the proviso that when in formula (VIa):

Ring A is pyridin-2-yl or thiazol-2-yl;

L¹ is —O—;

L² is —O—; and

R² is (C₁-C₆)alkyl, —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), or —(CR⁵R⁶)_(v)(4-12)-membered heterocyclyl; then

R² is further substituted by R¹¹ substituents each independently selected from —SO₂—(C₁-C₆)alkyl, —S(O)_(j)R¹², —S(O)_(k)NR⁸R⁹, —S(O)_(k)NR⁸R¹², —(C═O)—R¹², —(C═O)—NR⁸R⁹, or —(C═O)—NR⁸R¹². In the compounds of formula (VIa), preferably R¹¹ is —SO₂—CH₃; preferably R² is phenyl.

In another embodiment, the invention relates to compounds of the formula (I) selected from the group consisting of (VIIa), (VIIb), (VIIc) and (VIId):

wherein L is —O—, —NR⁵—, or —S—; and

wherein L², R¹, R², R³, ring A, w, and n are as defined above.

In another embodiment, the invention relates to compounds of the formula (I) selected from the group consisting of (VIIIa), (VIIIb), (VIIIc) and (VIIId):

wherein L is wherein L¹ is —O—, —NR⁵—, or —S—; and

wherein L², R¹, R², R³, ring A, w, and n are as defined above.

In another embodiment, the invention relates to compounds of the formula (I) selected from the group consisting of (IXa), (IXb), (IXc), and (IXd):

wherein

L is —O—, —NR⁵—, or —CR⁵R⁶;

L², R¹, R², R³, ring A, w, m, and n are as defined above;

and wherein the ring containing L¹ and —C═O— further contains an optional double bond.

In another embodiment, the invention relates to compounds of the formula (I) wherein said Ring C optionally contains a double bond. Specific embodiments within this embodiment include compounds of formula (II), such as formulae (IIb) or (IIc); compounds of formula (III), such as formulae (IIIb) or (IIIc); compounds of formula (IV), such as formulae (IVb) or (IVc); compounds of formula (V), such as formulae (Vb) or (Vc); compounds of formulae (VIa), (VIb), (VIc), (VId); compounds of formulae (VIIa), (VIIb), (VIIc), (VIId); compounds of formulae (VIIIa), (VIIIb), (VIIIc), (VIIId); and compounds of formulae (IXa), (IXb), (IXc), (IXd).

In another embodiment, the invention relates to compounds of the formula (I) wherein R² is (C₁-C₆)alkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), or —(CR⁵R⁶)_(v)(4-12)-membered heterocyclyl.

In another embodiment, the invention relates to compounds of the formula (I) wherein R³ is halo, cyano, CF₃, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, —(C═O)—R⁵, —(C═O)—O—R⁵, —O—(C═O)—R⁵, —NR⁵(C═O)—R⁷, —(C═O)—NR⁵R⁶, —NR⁵R⁶, or —NR⁵OR⁶.

In another embodiment, the invention relates to compounds of the formula (I) wherein each of R⁵, R⁶ and R⁷ are independently selected from H and (C₁-C₆)alkyl.

In another embodiment, the invention relates to compounds of the formula (I) wherein any carbon atoms of the (C₁-C₆)alkyl, the (3-10)-membered cycloalkyl, the (C₆-C₁₀)aryl and the (4-10)-membered heterocyclyl of the foregoing R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are optionally substituted with 1 to 3 substituents each independently selected from halo, hydroxyl, cyano, —(C═O)—R⁸, (C₁-C₆)alkoxy, and —S(O)_(j)(C₁-C₆)alkyl.

In another embodiment, the invention relates to compounds of any of the above embodiments, wherein L¹ is —O—.

In another embodiment, the invention relates to compounds of any of the above embodiments, wherein each of R¹ and R⁴ are independently selected from H or (C₁-C₆)alkyl.

In another embodiment, the invention relates to compounds of any of the above embodiments, wherein each of R¹ and R⁴ are independently selected from H, halo, —CHF₂, —CH₂F, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, —(C═O)—R⁵, —(C═O)—NR⁵R⁶, —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), and —(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl.

In another embodiment, the invention relates to compounds of any of the above embodiments, wherein R² is H, (C₁-C₆)alkyl, —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), or —(CR⁵R⁶)_(v)(4-12)-membered heterocyclyl.

In another embodiment, the invention relates to compounds of any of the above embodiments, wherein m is 1 or 2.

In another embodiment, the invention relates to compounds of any of the above embodiments, wherein R³ is H, cyano, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, —(C═O)—R⁵, —(C═O)—O—R⁵, —O—(C═O)—R⁵, —NR⁵(C═O)—R⁶, —(C═O)—NR⁵R⁶, —NR⁵R⁶, —NR⁵OR⁶, or —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl.

In another embodiment, the invention relates to compounds of any of the above embodiments, wherein each of R5, R⁶ and R⁷ are independently selected from H and (C₁-C₆)alkyl.

In another embodiment, the invention relates to compounds of any of the above embodiments, wherein R¹¹ is selected from halo, cyano, —CHF₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, —(C═O)—R⁸, —(C═O)—R¹², —O—R¹², —(C═O)—NR⁸R⁹, —(C═O)—NR⁸R¹², —NR⁸R⁹, —NR⁸R¹², —S(O)_(j)(C₁-C₆)alkyl, —S(O)_(j)R¹², —S(O)_(k)NR⁸R⁹, —S(O)_(k)NR⁸R¹², —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), and —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl.

Specific Embodiments of Compounds of the Invention are Selected from the Group Consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to pharmaceutical composition comprising an effective amount of a compound of formula formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating a condition that is mediated by the modulation of GK, the method comprising administering to a mammal an effective amount of a compound of formula formula (I), or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to a method of treating a condition that is mediated by the modulation of GK, the method comprising administering to a mammal an amount of a compound of formula formula (I), or a pharmaceutically acceptable salt or solvate thereof, effective to lower blood glucose levels.

The present invention also relates to a method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, ophthalmic diseases, diabetic retinopathy, diabetic macular edema, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound of formula formula (I), or a pharmaceutically acceptable salt or solvate thereof.

The present invention also relates to a method of treating a condition, the method comprising administering to a mammal an amount effective of a compound of formula formula (I), or a pharmaceutically acceptable salt or solvate thereof, effective to lower blood glucose levels.

DEFINITIONS

For purposes of the present invention, as described and claimed herein, the following terms are defined as follows:

As used herein, the terms “comprising”, “including”, or “having” are used in their open, non-limiting sense.

The term “halo”, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.

The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.

The term “alkenyl”, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.

The term “alkynyl”, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.

The term “alkoxy”, as used herein, unless otherwise indicated, includes 0-alkyl groups wherein alkyl is as defined above.

The term “Me” means methyl, “Et” means ethyl, and “Ac” means acetyl.

The term “cycloalkyl”, as used herein, unless otherwise indicated refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl. Illustrative examples of cycloalkyl are derived from, but not limited to, the following:

The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.

The term “(4-12)-membered heterocyclyl” or “(4-10)-membered heterocyclyl”, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 3-7, 6-10, or 4-10 atoms, respectively, in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). The 4-7 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring. An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl. Other Illustrative examples of 4-7 membered heterocyclic are derived from, but not limited to, the following:

Unless otherwise indicated, the term “oxo” refers to ═O.

A “solvate” is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula (I). The compounds of formula (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.

The term “diseases in which the liver is a target organ”, as used herein, unless otherwise indicated means diabetes, hepatitis, liver cancer, liver fibrosis, and malaria.

The term “Metabolic syndrome”, as used herein, unless otherwise indicated means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.

In the compounds of formula (I), where terms such as (CR⁵R⁶)_(v) or (CR⁸R⁹), are used, R⁵, R⁶, R⁸and R⁹ may vary with each iteration of v or p. For instance, where v or p is 2 the terms (CR⁵R⁶)_(v) or (CR⁸R⁹)_(p) may equal —CH₂CH₂—, or —CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)—, or any number of similar moieties falling within the scope of the definitions of R⁵, R⁶, R⁸and R⁹.

The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above.

The term “modulate” or “modulating”, as used herein, refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.

The term “obesity” or “obese”, as used herein, refers generally to individuals who are at least about 20-30% over the average weight for his/her age, sex and height. Technically, “obese” is defined, for males, as individuals whose body mass index is greater than 27.8 kg/m², and for females, as individuals whose body mass index is greater than 27.3 kg/m². Those of skill in the art readily recognize that the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.

The term “inflammatory disorders”, as used herein, refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.

The phrase “therapeutically effective amount”, as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.

The phrase “amount . . . effective to lower blood glucose levels”, as used herein, refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in the range of about 10 nM up to 2 μM; with concentrations in the range of about 100 nM up to 500 nM being preferred. As noted previously, since the activity of different compounds which fall within the definition of Formula (I) as set forth above may vary considerably, and since individual subjects may present a wide variation in severity of symptoms, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly.

The phrase “insulin resistance”, as used herein, refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.

The phrase “insulin resistance syndrome”, as used herein, refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.

Certain compounds of formula (I) may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula (I), the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.

Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.

The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of the present invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula (I) of this invention thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

Other aspects, advantages, and features of the invention will become apparent from the detailed description below.

DETAILED DESCRIPTION AND EMBODIMENTS OF THE INVENTION

The schemes below describe and depict general routes to prepare specific examples of the present invention of formula (I) wherein the definitions of are given in the summary of the invention.

As depicted in Scheme A, following procedures described elsewhere and known to those skilled in the art, reactions of ester A-1 or A-4 or other ester derivatives thereof with R²-X², wherein X² is a leaving group that could be displaced by X¹, or X¹ is a leaving group that could be displaced by X², provide ester A-2 or A-5 or other ester derivatives thereof. Reactions of ester A-2 or A-5 or other ester derivatives thereof with heteroaryl amine A-7 and dimethylaluminum chloride in dichloromethane could directly generate corresponding amides A-3 or A-6. A-3 or A-6 could also be obtained by hydrolysis of ester A-2 or A-5 or other ester derivatives thereof to acids and followed by amide formation by procedures known to those skilled in the art.

Alternatively, as depicted in Scheme B, ester A-1 or A-4 or other ester derivatives thereof could be coupled to heteroaryl amine A-7 to generate amides B-1 or B-2. B-1 or B-2 could then be reacted with R²-X² replacing suitable leaving groups to provide A-3 and A-6, following procedures known to those skilled in the art.

Specific examples of intermediate A-1 and A-4 as described in Schemes A and B above can be prepared using the procedures as described in the following schemes:

As depicted in Scheme C, dihydrobenzofuran intermediates C-8 or C-9 could be prepared starting from commercially available methyl 3,5-dihydroxybenzoate (C-1). Following procedures known to those skilled in the art, alkylation of C-1 with suitable allyl halides under basic conditions such as K₂CO₃ or Cs₂CO₃ in DMF gives C-2; the phenol group in C-2 could be protected by suitable protecting groups such as MOM or methyl ether to provide C-3 (see Protective Groups in Organic Synthesis, Greene & Wuts, Wiley Interscience, New York, 3^(rd) edition, 1999). Claisen rearrangements of C-3 under conditions such as heating in dimethyl aniline yield C-4 or C-5. Treatment of C-4 or C-5 with Lewis acids such as zirconium(IV) chloride gives dihydrobenzofuran intermediate C-6 or C-7. Following procedures known to those skilled in the art, the protecting groups in C-6 or C-7 could be removed to yield phenol intermediate C-8 or C-9.

Alternatively, as depicted in Scheme D, dihydrobenzofuran intermediate C-8 could be prepared starting from commercially available 4-bromo-3,5-dihydroxybenzoic acid (D-1). Following procedures known to those skilled in the art, D-1 could be converted to its methyl ester D-2, such as refluxing in methanol with catalytic H₂SO₄. The phenol groups in D-2 could be protected by suitable protecting groups such as MOM or methyl ether to provide D-3. D-3 could be coupled to allyltributyltins with suitable catalysts such as PdCl₂ with suitable phosphine ligand and CuI to generate D-4. D-4 could be converted directly to C-8 under acidic conditions such as refluxing in MeOH/HCl or could be converted to D-5 through standard protecting group removal procedure followed by ring closure to give C-8.

As depicted in Scheme E, dihydrobenzofuran intermediate E-5 could be prepared starting from commercially available methyl 3,5-dihydroxybenzoate (C-1). Following procedures known to those skilled in the art, one of the phenol groups in C-1 could be protected by suitable protecting groups such as MOM or methyl ether to provide E-1. Alkylation of E-1 with bromoacetaldehyde diethyl acetal under basic conditions such as NaH in DMF gives E-2. Heating E-2 in polyphosphoric acid and benzene generates benzofuran intermediate E-3. The protecting group in E-3 could be removed under standard conditions known to those skilled in the art to provide E-4. E-4 could be subjected to hydrogenation conditions to provide dihydrobenzofuran E-5.

As depicted in Scheme F, dihydrobenzofuran intermediate F-3 could be prepared starting from commercially available 2-furaldehyde and diethyl succinate. Treatment of 2-furaldehyde and diethyl succinate with potassium t-butoxide in refluxing t-butanol gives intermediate F-1. Treatment of F-1 with sodium acetate in refluxing acetic anhydride, followed by aqueous work-up and subsequently refluxing the residue in EtOH in the presence of K₂CO₃, gives benzofuran F-2. F-2 could be subjected to hydrogenation conditions to provide dihydrobenzofuran F-3.

As depicted in Scheme G, tetrahydrobenzopyran intermediate G-3 and G-4 could be prepared starting from commercially available methyl 3,5-dihydroxybenzoate (C-1). Alkylation of C-1 with 1-bromo-3-methyl-but-2-ene under basic conditions such as potassium carbonate in DMF gives G-1. Under conditions known to those skilled in the art, G-1 could be reacted with R²-X², wherein X² is a leaving group that could be displaced by phenol in G-1 to give G-2. Treatment of G-2 with Montarillonite K10 yielded tetrahydrobenzopyran intermediates G-3 and G-4.

When R₃ in any specific examples is a carboxylic acid, as depicted in Scheme H, H-2 could be prepared from hydrolysis of the corresponding esters under basic conditions such as treatment of H-1 with aqueous NaOH in THF. H-1 could be prepared following Schemes A-G.

Any of the above compounds described in schemes A-H can be converted into another analogous compound by standard chemical manipulations. These chemical manipulations are known to those skilled in the art and include a) removal of a protecting group by methods outlined in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, New York, 1991; b) displacement of a leaving group (halide, mesylate, tosylate, etc) with a primary or secondary amine, thiol or alcohol to form a secondary or tertiary amine, thioether or ether, respectively; c) treatment of phenyl (or substituted phenyl) carbamates with primary of secondary amines to form the corresponding ureas as in Thavonekham, B., et al., Synthesis (1997), 10,189; d) reduction of propargyl or homopropargyl alcohols or N-BOC protected primary amines to the corresponding E-allylic or E-homoallylic derivatives by treatment with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) as in Denmark, S. E.; Jones, T. K. J., Org. Chem. (1982) 47, 4595-4597 or van Benthem, R. A. T. M.; Michels, J. J.; Speckamp, W. N. Synlett (1994), 368-370; e) reduction of alkynes to the corresponding Z-alkene derivatives by treatment hydrogen gas and a Pd catalyst as in Tomassy, B., et. al., Synth. Commun. (1998), 28, 1201 f) treatment of primary and secondary amines with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl/aryl chloroformate or sulfonyl chloride to provide the corresponding urea, amide, carbamate or sulfonamide; g) reductive amination of a primary or secondary amine using R¹CH(O); and h) treatment of alcohols with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl/aryl chloroformate or sulfonyl chloride to provide the corresponding carbamate, ester, carbonate or sulfonic acid ester.

The compounds of the present invention may have asymmetric carbon atoms. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.

The compounds of formulas (I) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.

Those compounds of formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I). Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

The compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (Xth ed.).

Pharmaceutical Compositions/Formulations, Dosaging and Modes of Administration

Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. In addition, those of ordinary skill in the art are familiar with formulation and administration techniques. Such topics would be discussed, e.g. in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, current edition, Pergamon Press; and Remington's Pharmaceutical Sciences, current edition. Mack Publishing, Co., Easton, Pa. These techniques can be employed in appropriate aspects and embodiments of the methods and compositions described herein. The following examples are provided for illustrative purposes only and are not meant to serve as limitations of the present invention.

The amino heterocyclyl compounds of formula (I) may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of GK mediated diseases. The compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs. The compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets. As is conventional in the art these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.

Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan monooleate.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables.

The amino heterocyclyl compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and other glycerides.

For topical use preparations, for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed.

The amino heterocyclyl compounds of formula (I) may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles. Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.

Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight. A preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. To enhance the therapeutic activity of the present compounds they may be administered concomitantly with other orally active antidiabetic compounds such as the sulfonylureas, for example, tolbutamide and the like.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

The invention will now be described in reference to the following Examples. These Examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner.

EXAMPLES

In the examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents may be purchased from commercial suppliers, such as Sigma-Aldrich Chemical Company, Acros Organics, or Lancaster Synthesis Ltd. and may be used without further purification unless otherwise indicated. Tetrahydrofuran (THF), methylene chloride (CH₂Cl₂), and N,N-dimethylformamide (DMF) may be purchased from Aldrich in Sure-Seal bottles and used as received. All solvents may be purified using standard methods known to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally under a positive pressure of argon or nitrogen or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed using glass-backed silica gel 60 F 254 precoated plates (Merck Art 5719) and eluted with appropriate solvent ratios (v/v). Reactions were assayed by TLC or LCMS and terminated as judged by the consumption of starting material. Visualization of the TLC plates was done with UV light (254 nM wavelength) or with an appropriate TLC visualizing solvent and activated with heat. Flash column chromatography (Still et al., J. Org. Chem. (1978) 43, 2923) was performed using silica gel 60 (Merck Art 9385) or various MPLC systems, such as Biotage or ISCO purification system.

The compound structures in the examples below were confirmed by one or more of the following methods: proton magnetic resonance spectroscopy, mass spectroscopy, and elemental microanalysis. Proton magnetic resonance (¹H NMR) spectra were determined using a Bruker spectrometer operating at a field strength of 300 or 400 megahertz (MHz). Chemical shifts are reported in parts per million (PPM, δ) downfield from an internal tetramethylsilane standard. Alternatively, ¹H NMR spectra were referenced to signals from residual protons in deuterated solvents as follows: CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm; C₆D₆=7.16 ppm; CD₃OD=3.30 ppm. Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS) data were obtained using Agilent mass spectrometer with APCI or ESI ionization. Elemental microanalyses were performed by Atlantic Microlab Inc. and gave results for the elements stated within ±0.4% of the theoretical values.

Preferred compounds in accordance with the invention may be prepared in manners analogous to those specifically described below.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. The skilled artisan will recognize that different acids, amines, alkyl halides, aryl halides, coupling reagents, and heterocycles may be substituted in the following descriptions to suit the preparations of a desired embodiment. The following methods may be scaled upwards or downwards to suit the amount of desired material.

In the examples and specification, “Et” means ethyl, “Ac” means acetyl, “Me” means methyl, “ETOAC” or “EtOAc” means ethyl acetate, “THF” means tetrahydrofuran, and “Bu” means butyl. Et₂O refers to diethyl ether. DMF refers to N,N-dimethylformamide. DMSO refers to dimethylsulfoxide. MTBE refers to tert-butyl methylether. Other abbreviations include: CH₃OH or Me0H (methanol), EtOH (ethanol), DME (ethylene glycol dimethyl ether), DCM or CH₂Cl₂ (dichloromethane or methylene chloride), CHCl₃ (chloroform), 1,2-DCE (1,2-dichloroethane), Ph (phenyl), TFA (trifluoroacetic acid), DIEA (N,N-diisopropylethylamine), TEA or Et₃N (triethylamine), NMM (4-methylmorpholine), HOBt (1-hydroxybenzotriazole hydrate), HATU [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate], EDCI [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride], DCC (dicyclohexyl carbodiimide), DMAP (4-dimethylaminopyridine), NaOH (sodium hydroxide), KOH (potassium hydroxide), HCl (hydrogen chloride), MgSO₄ (magnesium sulfate), Na₂SO₄ (sodium sulfate), NH₄Cl (ammonium chloride), and NaHCO₃ (sodium bicarbonate).

Example 1 6-(4-Methanesulfonyl-phenoxy)-2-methyl-2,3-dihydrobenzofuran-4-carboxylic acid pyridin-2-ylamide

Dimethylaluminum chloride (1.0 M solution in hexanes, 3 mL, 3.0 mmol) was added to a solution of 2-aminopyridine (282 mg, 3.0 mmol) in 1,2-dichloromethane at 0° C. The mixture was stirred at room temperature for 15 min and then 6-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1f) (108 mg, 0.30 mmol) in 1,2-dichloromethane (3 mL) was added. The mixture was stirred at room temperature overnight, and carefully quenched with 20% aqueous potassium sodium tartrate tetrahydrate (5 mL), diluted with H₂O (30 mL), extracted with CH₂Cl₂ (2×50 mL) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 50% EtOAc in hexane to give a white solid (67 mg, 53% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (br. s., 1 H) 8.21-8.34 (m, 2 H) 7.87-7.96 (m, 2 H) 7.70-7.81 (m, 1 H) 7.04-7.17 (m, 3 H) 6.94 (d, J=2.02 Hz, 1 H) 6.67 (d, J=1.77 Hz, 1 H) 4.97-5.18 (m, 1 H) 3.71 (dd, J=16.67, 8.84 Hz, 1 H) 3.19 (dd, J=16.67, 7.58 Hz, 1 H) 3.07 (s, 3 H) 1.53 (d, J=6.32 Hz, 3 H); LCMS for C₂₂H₂₀N₂O₅S m/z 425.10 (M+H)⁺; Anal. Calcd. for C₂₂H₂₀N₂O₅S.0.2 H₂O: C, 61.73; H, 4.80; N, 6.54; Found: C, 61.71; H, 4.81; N, 6.41.

Preparation of Intermediate 1a 3-Allyloxy-5-hydroxy-benzoic acid methyl ester

Methyl 3,5-dihydroxybenzoate (20.9 g, 124 mmol) was dissolved in DMF (30 mL). Potassium carbonate (34.4 g, 249 mmol) was added, followed by allyl bromide (10.5 mL, 124 mmol). The resulting suspension was stirred at room temperature overnight under argon atmosphere. The reaction mixture was quenched with H₂O, extracted with EtOAc (2×150 mL). The organic layers were washed with H₂O (2×200 mL), dried with MgSO₄ and concentrated in vacuo to yield a pale yellow oil which was purified by flash column chromatography eluting with 20% EtOAc in hexane to give a pale yellow solid (10.25 g, 40% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.08-7.22 (m, 2 H) 6.65 (t, J=2.40 Hz, 1 H) 5.94-6.21 (m, 1 H) 5.73 (s, 1 H) 5.42 (dd, J=17.18, 1.52 Hz, 1 H) 5.31 (dd, J=10.48, 1.39 Hz, 1 H) 4.55 (d, J=5.05 Hz, 2 H) 3.91 (s, 3 H); LCMS for C₁₄H₁₂O₄ m/z 209.0 (M+H)⁺.

Preparation of Intermediate 1b 3-Allyloxy-5-methoxy-benzoic acid methyl ester

To a solution of 3-allyloxy-5-hydroxy-benzoic acid methyl ester (la) (10.25 g, 49.2 mmol) in DMF (20 mL) was added methyl iodide (3.67 mL, 59.1 mmol) and K₂CO₃ (13.6 g, 98.5 mmol). The reaction mixture was stirred at 70° C. for 2 hr, cooled to room temperature. The mixture was quenched with H₂O (150 mL) and extracted with EtOAc (2×150 mL). The organic layers were washed with H₂O (2×150 mL), dried over MgSO₄ and concentrated to give a pale yellow oil which was purified by flash column chromatography eluting with 10% EtOAc in hexane to give a colorless oil (9.63 g, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.24 (m, 2 H) 6.68 (t, J=2.40 Hz, 1 H) 5.91-6.17 (m, 1 H) 5.38-5.51 (m, 1 H) 5.31 (dd, J=10.48, 1.39 Hz, 1 H) 4.52-4.61 (m, 2 H) 3.91 (s, 3 H) 3.83 (s, 3 H); LCMS for C₁₂H₁₄O₄ m/z 223.0 (M+H)⁺.

Preparation of Intermediate 1c Mixture of 2-allyl-3-hydroxy-5-methoxy-benzoic acid methyl ester and 4-allyl-3-hydroxy-5-methoxy-benzoic acid methyl ester

3-Allyloxy-5-methoxy-benzoic acid methyl ester (1b) (8.63 g, 38.8 mmol) was added to dimethyl aniline (20 mL). The mixture was heated to reflux overnight. The mixture was cooled to room temperature, quenched with 1N HCl (200 mL), extracted with EtOAc (2×200 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 5-20% EtOAc in hexanes to give a mixture of 2-allyl-3-hydroxy-5-methoxy-benzoic acid methyl ester and 4-allyl-3-hydroxy-5-methoxy-benzoic acid methyl ester as a pale yellow solid (5.1 g, 59% yield) ¹H NMR (400 MHz, CDCl₃) δ 7.21 (s, 1 H) 7.17 (s, 1 H) 6.98 (d, J=2.53 Hz) 6.60 (d, J=2.53 Hz) 5.85-6.13 (m) 5.58 (s) 5.66 (s), 5.11 (s), 5.07-5.09 (m) 3.91 (s) 3.88 (s) 3.86 (s) 3.79 (s) 3.68 (d, J=5.81 Hz) 3.48 (d, J=5.81 Hz). LCMS for C₁₂H₁₄O₄ m/z 223.0 (M+H)⁺.

Preparation of Intermediate 1d Mixture of 4-methoxy-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester

Zirconium(IV) chloride (4.83 g, 20.7 mmol) was added to a mixture of 2-allyl-3-hydroxy-5-methoxy-benzoic acid methyl ester and 4-allyl-3-hydroxy-5-methoxy-benzoic acid methyl ester (1c) (3.84 g, 17.3 mmol) in CH₂Cl₂ (60 mL) at 0° C. The mixture was stirred at 0° C. and warmed to room temperature overnight, quenched with H₂O (100 mL) and extracted with CH₂Cl₂ (2×100 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 5-10% EtOAc in hexanes to give a mixture of methyl 6-methoxyl-2-methyl-2,3-dihydrobenzofuran-4-carboxylate and methyl 4-methoxyl-2-methyl-2,3-dihydrobenzo-furan-6-carboxylate (1:1) as colorless oil (1.91 g, 22% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J=16.17 Hz) 7.03 (d, J=2.53 Hz) 6.54 (d, J=2.27 Hz) 4.92-5.03 (m) 3.86-3.91 (m) 3.81 (s) 3.59 (dd, J=16.93, 8.84 Hz) 3.30 (dd, J=16.29, 8.97 Hz) 3.05 (dd, J=16.80, 7.45 Hz) 2.77 (dd, J=16.17, 7.33 Hz) 1.59 (s) 1.47 (d, J=6.32 Hz).); LCMS for C₁₂H₁₄0₄ m/z 223.0 (M+H)⁺.

Preparation of Intermediate 1e 6-Hydroxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester

2,6-Lutidine (2.64 mL, 22.7 mmol) and BBr₃ (22.7 mL, 22.7 mmol, 1.0 M solution in CH₂Cl₂) were added to a mixture of 4-methoxy-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1d) (1.68 g, 7.58 mmol) in CH₂Cl₂ (30 mL) at 0° C. The mixture was stirred at 0° C. and the warmed to room temperature overnight. The mixture was quenched with H₂O (80 mL) and extracted with CH₂Cl₂ (2×80 mL). The organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 20-30% EtOAc in hexanes to give a pale brown colored solid (366 mg, 23% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.99 (d, J=2.27 Hz, 1 H) 6.49 (d, J=2.27 Hz, 1 H) 5.46 (s, 1 H) 4.86-5.07 (m, 1 H) 3.89 (s, 3 H) 3.57 (dd, J=16.93, 8.84 Hz, 1H) 3.03 (dd, J=16.93, 7.33 Hz, 1 H) 1.46 (d, J=6.32 Hz, 3 H); LCMS for C₁₁H₁₂O₄ m/z 209.0 (M+H)⁺.

Preparation of Intermediate 1f 6-(4-Methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester

4-Fluorophenyl methyl sulfone (307 mg, 1.76 mmol) and Cs₂CO₃ (1.15 g, 3.52 mmol) were added to a solution of 6-hydroxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1e) (366 mg, 1.76 mmol) in DMF (8 mL). The mixture was heated to 120° C. for 1 hr, cooled to room temperature, quenched with H₂O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with H₂O (2×80 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 40% EtOAc in hexanes to give a pale brown solid (350 mg, 55% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.93 (m, 2 H) 7.18 (d, J=2.02 Hz, 1 H) 7.04-7.14 (m, 2 H) 6.67 (d, J=2.27 Hz, 1 H) 4.94-5.17 (m, 1 H) 3.89 (s, 3 H) 3.68 (dd, J=17.43, 8.84 Hz, 1 H) 3.13 (dd, J=17.43, 7.58 Hz, 1 H) 3.07 (s, 3H) 1.51 (d, J=6.32 Hz, 3 H);); LCMS for C₁₈H₁₈O₆S m/z 363.0 (M+H)⁺.

Example 2 6-(4-Methanesulfonyl-phenoxy)-2-methyl-2,3-dihydrobenzofuran-4-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 6-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1f) to give a white solid (92 mg, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.33 (br. s., 1 H) 8.20 (d, J=8.34 Hz, 1 H) 8.10 (d, J=2.27 Hz, 1 H) 7.86-7.96 (m, 2 H) 7.57 (dd, J=8.59, 2.27 Hz, 1 H) 7.09-7.14 (m, 2 H) 6.93 (d, J=2.02 Hz, 1 H) 6.66 (d, J=2.02 Hz, 1 H) 4.93-5.19 (m, 1 H) 3.70 (dd, J=16.80, 8.97 Hz, 1 H) 3.18 (dd, J=16.93, 7.58 Hz, 1 H) 3.07 (s, 3 H) 2.32 (s, 3 H) 1.52 (d, J=6.32 Hz, 3 H); LCMS for C₂₃H₂₂N₂O₅S m/z 439.1 (M+H)⁺; Anal. Calcd. for C₂₃H₂₂N₂O₅S: C, 63.09; H, 5.06; N, 6.39; Found: C, 62.90; H, 5.06; N, 6.32.

Example 3 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3f) to give a white solid (71 mg, 65% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1 H) 8.22 (d, J=8.34 Hz, 1 H) 8.11 (s, 1 H) 7.93 (d, J=8.59 Hz, 2 H) 7.57 (d, J=8.34 Hz, 1 H) 7.13 (d, J=8.84 Hz, 2 H) 7.10 (s, 2 H) 3.09 (s, 3H) 2.91 (s, 2 H) 2.32 (s, 3 H) 1.51 (s, 6 H); LCMS for C₂₄H₂₄N₂O₅S m/z 453.10 (M+H)⁺; Anal. Calcd. for C₂₄H₂₄N₂O₅S.0.3 CH₂Cl₂: C, 61.06; H, 5.19; N, 5.86; Found: C, 60.97; H, 5.07; N, 5.94.

Preparation for Intermediate 3a 3-Hydroxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (15.0 g, 89.2 mmol), potassium carbonate (24.7 g, 178.4 mmol) and 3-bromo-2-methyl-propene (9.0 mL, 89.2 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.80 g, 39% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.22 (m, 2 H) 6.66 (t, J=2.27 Hz, 1 H) 5.81 (s, 1 H) 5.06-5.16 (m, 1H) 4.93-5.04 (m, 1H) 4.44 (s, 2 H) 3.91 (s, 3 H) 1.68-1.94 (m, 3 H); LCMS for C₁₂H₁₄O₄ m/z 223.10 (M+H)⁺.

Preparation of Intermediate 3b 3-Methoxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1b, from 3-methoxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester (3a) (7.80 g, 35.0 mmol), methyl iodide (2.60 mL, 42.0 mmol) and K₂CO₃ (9.67 g, 70.0 mmol). Purification by column chromatography eluting with 10% EtOAc in hexanes gave a colorless oil (7.54 g, 91% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.22 (m, 1 H) 7.18-7.20 (m, 1 H) 6.68 (t, J=2.27 Hz, 1 H) 5.11 (s, 1 H) 5.01 (s, 1 H) 4.46 (s, 2H) 3.91 (s, 3 H) 3.83 (s, 3H) 1.84 (s, 3 H); LCMS for C₁₃H₁₆O₄ m/z 237.10 (M+H)⁺.

Preparation of Intermediate 3c Mixture of 3-hydroxy-5-methoxy-2-(2-methyl-allyl)-benzoic acid methyl ester and 3-hydroxy-5-methoxy-4-(2-methyl-allyl)-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1c, from 3-methoxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester (3b) (7.54 g, 32.0 mmol). Purification by column chromatography eluting with 5-20% EtOAc in hexanes gave a mixture of 3-hydroxy-5-methoxy-2-(2-methyl-allyl)-benzoic acid methyl ester and 3-hydroxy-5-methoxy-4-(2-methyl-allyl)-benzoic acid methyl ester as a colorless oil (4.80 g, 64% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.24 (m) 7.02 (d, J=2.27 Hz) 6.68 (t, J=2.40 Hz) 6.51 (d, J=2.27 Hz) 5.10 (s) 5.00 (s) 3.91 (s) 3.88 (s) 3.83 (s) 3.80 (s) 3.26 (s) 1.83 (s) 1.47 (s); LCMS for C₁₃H₁₆O₄ m/z 237.10 (M+H)⁺.

Preparation of Intermediate 3d Mixture of 4-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester and 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1d, from zirconium(IV) chloride (3.03 g, 11.0 mmol) and a mixture of methyl 2-ally-3-hydroxy-5-methoxy-benzoate and methyl 2-ally-3-hydroxy-5-methoxybenzoate (3c) (2.5 g, 13.0 mmol). Purification by column chromatography eluting with 5-10% EtOAc in hexanes gave a mixture of 4-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester (2:1) as a colorless oil (1.74 g, 70% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.12 (s) 7.07 (s) 7.03 (d, J=2.27 Hz) 6.52 (d, J=2.27 Hz) 3.90 (s) 3.87 (s) 3.81 (s) 3.27 (s) 2.97 (s) 1.49 (s) 1.48 (s); LCMS for C₁₃H₁₆O₄ m/z 237.10 (M+H)⁺.

Preparation of Intermediate 3e 4-Hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxy-lic acid methyl ester

To the mixture of 4-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (3d) (1.74 g, 7.36 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added BBr₃ (22.0 mL, 22 mmol, 1.0 M solution in CH₂Cl₂). The reaction mixture was stirred at 0° C. for 6 hr, quenched with H₂O (100 mL), extracted with CH₂Cl₂ (2×100 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 10% EtOAc in hexanes to give an pale yellow solid (171 mg, 10% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.15 (s, 1 H) 6.99 (s, 1 H) 5.87 (s, 1H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.50 (s, 6 H); LCMS for C₁₂H₁₄O₄ m/z 223.0 (M+H)⁺.

Preparation of Intermediate 3f 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (115 mg, 0.77 mmol), Cs₂CO₃ (507 mg, 1.54 mmol), and methyl 6-hydroxyl-2-methyl-2,3-dihdrovenzofuran-4-carboxylate (3e) (171 mg, 0.77 mmol). Purification by column chromatography eluting with 15-40% EtOAc in hexanes gave a pale brown solid (230 mg, 79% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.88-7.94 (m, 2 H) 7.09 (d, J=2.53 Hz, 1 H) 7.05 (d, J=8.84 Hz, 2 H) 6.66 (d, J=2.53 Hz, 1 H) 3.81 (s, 3 H) 3.07 (s, 3 H) 2.92 (s, 2 H) 1.33 (s, 6 H); LCMS for C₁₉H₂₀O₆S m/z 377.10 (M+H)⁺.

Alternative method to prepare Intermediate 3e Preparation of Intermediate 3g 4-Bromo-3,5-dihydroxybenzoic acid methyl ester

To a solution of 4-bromo-3,5-dihydroxybenzoic acid (13.89 g, 59.6 mmol) in methanol (50 mL) was added H₂SO₄ (concentrated, 1 mL). The reaction mixture was heated to reflux overnight. The mixture was quenched with H₂O (500 mL) and extracted with 10% MeOH in CH₂Cl₂ (5×500 mL), dried over MgSO₄ and concentrated in vacuo to give a white solid (14.8 g, 100% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 2 H) 7.00 (s, 2 H) 3.80 (s, 3 H); LCMS for C₈H₇BrO₄ m/z 249.10 (M+H)⁺.

Preparation of Intermediate 3h 4-Bromo-3,5-bis-methoxymethoxy-benzoic acid methyl ester

To a solution of 4-bromo-3,5-dihydroxybenzoic acid methyl ester (3g) (3.05 g, 12.3 mmol) in DMF (60 mL) at 0° C. was added NaH (1.47g, 40 mmol, 60% in mineral oil). The mixture was stirred at 0° C. for 30 min, and then chloromethyl methyl ether (2.80 mL, 36.9 mmol) was added. The mixture was stirred at 0° C. and then warmed to room temperature for 3 hr. The mixture was quenched with H₂O (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were wash with H₂O (2×150 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexanes to give a white solid (2.76 g, 67% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, 2 H) 5.32 (s, 4 H) 3.91 (s, 3 H) 3.54 (s, 6 H); LCMS for C₁₂H₁₆BrO₆ m/z 335.0 (M+H)⁺.

Preparation of Intermediate 3i 3,5-Bis-methoxymethoxy-4-(2-methyl-allyl)-benzoic acid methyl ester

To a solution of 4-bromo-3,5-bis-methoxymethoxy-benzoic acid methyl ester (3 h) (3.10 g, 9.25 mmol) in DMF (20 mL) was added CsF (2.80 g, 18.4 mmol), CuI (200 mg, 1.05 mmol), PdCl₂ (200 mg, 1.12 mmol), 2-methylallyltributyltin (3.80, 11.0 mmol) and PtBu₃ (220 mg, 1.09 mmol). The reaction mixture was degassed and heated to 45° C. overnight. The mixture was filtered through Celite, quenched with H₂O (100 mL), extracted with EtOAc (2×100 mL). The organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexanes to give the desired product as brown oil (3.6 g) which contained tin impurities. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.46 (m, 2 H) 5.22 (s, 4 H) 4.61-4.76 (m, 1 H) 4.38-4.55 (m, 1 H) 3.90 (s, 3 H) 3.47 (s, 6 H) 3.42-3.45 (m, 2 H) 1.80 (s, 3 H); LCMS for C₁₆H₂₂O₆ m/z 311.10 (M+H)⁺.

Preparation of Intermediate 3e 4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxy-lic acid methyl ester

To a solution of 3,5-bis-methoxymethoxy-4-(2-methyl-allyl)-benzoic acid methyl ester (3i) (3.6 g, 9.02 mmol) in methanol (5 mL) was added 1.3 mL concentrated aqueous HCl. The reaction mixture was heated to reflux for 1 hr, quenched with H₂O (100 mL), extracted with EtOAc (2×100 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexane to give a pale yellow solid (1.08 g, 54% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.12 (d, J=1.26 Hz, 1 H) 7.00 (d, J=1.01 Hz, 1 H) 5.63 (s, 1 H) 3.89 (s, 3 H) 3.00 (s, 2H) 1.50 (s, 6 H); LCMS for C₁₂H₁₄O₄ m/z 223.10 (M+H)⁺.

Example 4 5-(4-Methanesulfonyl-phenoxy)-2-methyl-benzofuran-7-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 5-(4-methanesulfonyl-phenoxy)-2-methyl-benzofuran-7-carboxylic acid methyl ester (4e). ¹H NMR (400 MHz, CDCl₃) δ 9.63 (s, 1 H) 7.88 (d, J=8.84 Hz, 2 H) 7.81 (d, J=2.53 Hz, 1 H) 7.38 (d, J=2.53 Hz, 1 H) 7.33 (d, J=2.27 Hz, 1 H) 7.08 (d, J=8.84 Hz, 2 H) 6.86 (d, J=2.27 Hz, 1 H) 6.52 (s, 1H) 3.88 (s, 3 H) 3.06 (s, 3 H) 2.62 (s, 3H); LCMS for C₂₁H₁₉N₃O₅S m/z 426.00 (M+H)⁺; Anal. Calcd. for C₂₁H₁₉N₃O₅S: C, 59.28; H, 4.50; N, 9.88; Found: C, 59.11; H, 4.38; N, 9.80.

Preparation of Intermediate 4a 2-Allyloxy-5-methoxy-benzoic acid methyl ester

K₂CO₃ (4.64 g, 33.6 mmol) and allyl bromide (1.56 mL, 18.5 mmol) were added to a solution of methyl 2-hydroxy-5-methoxybenzoate (2.5 mL, 16.8 mmol) in DMF (10 mL). The reaction mixture was heated to 60° C. for 1 h, and then quenched with H₂O (80 mL) and extracted with EtOAc (2×80 mL). The organic layers were washed with H₂O (150 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 5-10% EtOAc/hexane to give a colorless oil (3.07 g, 82%). ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J=3.28 Hz, 1 H) 6.98-7.03 (m, 1H) 6.90-6.94 (m, 1 H) 6.01-6.11 (m, 1 H) 5.44-5.51 (m, 1 H) 5.25-5.31 (m, 1 H) 4.57 (td, J=3.28, 1.52 Hz, 2 H) 3.91 (s, 3 H) 3.80 (s, 3 H).

Preparation of Intermediate 4b 3-Allyl-2-hydroxy-5-methoxy-benzoic acid methyl ester

The solution of 2-allyloxy-5-methoxy-benzoic acid methyl ester (4a) (3.07 g, 13.8 mmol) in DMF (1 mL) was heated to 200° C. overnight. The mixture was quenched with H₂O (80 mL) and extracted with EtOAc (2×80 mL). The organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 10% EtOAc/hexane to give a pale yellow color oil (1.48 g, 48%). ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J=3.28 Hz, 1 H) 6.99 (d, J=3.28 Hz, 1 H) 5.95-6.06 (m, 1 H) 5.04-5.16 (m, 2 H) 3.95 (s, 3 H) 3.78 (s, 3 H) 3.38-3.45 (m, 2 H)

Preparation of Intermediate 4c 5-Methoxy-2-methyl-benzofuran-7-carboxylic acid methyl ester

To a solution of 3-allyl-2-hydroxy-5-methoxy-benzoic acid methyl ester (4b) (1.48 g, 6.66 mmol) in DMF (30 mL) was added Cu(OAc)₂ (3.63 g, 19.98 mmol), LiCl (847 mg, 19.98 mmol) in H₂O (1 mL) and PdCl₂ (24 mg, 0.133 mmol). The reaction mixture was stirred at RT for 3 h, quenched with H₂O (100 mL) and NH₄OH (5 mL) and extracted with EtOAc (100 mL). The organic layer was washed with H₂O (100 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 10-15% EtOAc/hexane to give colorless oil (1.48 g, 48%). ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J=2.53 Hz, 1 H) 7.17 (d, J=2.53 Hz, 1 H) 6.36 (s, 1 H) 4.00 (s, 3 H) 3.87 (s, 3 H) 2.51 (s, 3 H)

Preparation of Intermediate 4d 5-Hydroxy-2-methyl-benzofuran-7-carboxylic acid methyl ester

BBr₃ (10 mL, 10.08 mmol, 1.0 M in CH₂Cl₂) was added drop-wise to a solution of 5-methoxy-2-methyl-benzofuran-7-carboxylic acid methyl ester (4c) (951 mg, 4.31 mmol) and 2,6-lutidine (1.17 mL, 10.08 mmol) in CH₂Cl₂ (20 mL) at 0° C. The mixture was stirred and warmed to RT overnight. The mixture was quenched with H₂O (60 mL) and extracted with CH₂Cl₂ (2×60 mL). The combined organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 5% CH₃OH/CH₂Cl₂ to afford a white solid (746 mg, 83%). ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J=2.53 Hz, 1 H) 7.13 (d, J=2.53 Hz, 1 H) 6.33 (d, J=1.01 Hz, 1 H) 5.50 (s, 1H) 4.00 (s, 3 H) 2.49 (d, J=1.01 Hz, 3H).

Preparation of Intermediate 4e 5-(4-Methanesulfonyl-phenoxy)-2-methyl-benzofuran-7-carboxylic acid methyl ester

Cs₂CO₃ (2.36 g, 7.24 mmol) and 4-flurophenyl methyl sulfone (631 mg, 3.62 mmol) were added to a solution of 5-hydroxy-2-methyl-benzofuran-7-carboxylic acid methyl ester (4d) (746 mg, 3.62 mmol) in DMF (5 mL). The mixture was heated to 120° C. overnight and then cooled to RT. The mixture was then quenched with H₂O (80 mL) and extracted with EtOAc 92×100 ml). The combined organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 4% CH₃OH/CH₂Cl₂ to afford brown color oil (1.2 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 2 H) 7.86-7.90 (m, 1 H) 7.58 (d, J=2.53 Hz, 1 H) 7.38 (d, J=2.53 Hz, 1 H) 7.05 (d, J=8.84 Hz, 1 H) 6.44 (s, 1H) 3.99 (s, 3 H) 3.05 (s, 3 H) 2.56 (s, 3 H); LCMS for C₁₈H₁₆O₆S m/z 361.00 (M+H)⁺.

Example 5 5-(4-Methanesulfonyl-phenoxy)-2-methyl-benzofuran-7-carboxylic acid pyridin-2-ylamide

The title compound was prepared in a similar manner as described for Example 1, from 5-(4-methanesulfonyl-phenoxy)-2-methyl-benzofuran-7-carboxylic acid methyl ester (4e). ¹H NMR (400 MHz, CDCl₃) δ 9.85 (s, 1 H) 8.38-8.45 (m, 2 H) 7.87-7.92 (m, 2 H) 7.82 (d, J=2.53 Hz, 1 H) 7.75-7.81 (m, 1H) 7.41 (d, J=2.53 Hz, 1 H) 7.07-7.14 (m, 3 H) 6.54 (d, J=1.01 Hz, 1 H) 3.07 (s, 3 H) 2.66 (s, 3 H); LCMS for C₂₂H₁₈N₂O₅S m/z 423.00 (M+H)⁺; Anal. Calcd. for C₂₂H₁₈N₂O₅S.0.15 H₂O: C, 62.15; H, 4.34; N, 6.59; Found: C, 62.02; H, 4.15; N, 6.69.

Example 6 6-(4-Methanesulfonyl-phenoxy)-2,3-dihydrobenzofuran-4-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from a mixture of 6-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester and 6-(4-methanesulfonyl-phenoxy)-benzofuran-4-carboxylic acid methyl ester (6f) to give a white solid (66 mg, 16% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1 H) 8.25 (d, J=8.59 Hz, 1 H) 8.06 (d, J=1.52 Hz, 1 H) 7.91 (m, 2 H) 7.60 (dd, J=8.59, 2.27 Hz, 1 H) 7.11-7.17 (m, 2 H) 7.00 (d, J=1.77 Hz, 1 H) 6.69 (d, J=1.77 Hz, 1 H) 4.71 (t, J=8.72 Hz, 2 H) 3.58 (t, J=8.72 Hz, 2 H) 3.06-3.09 (m, 3 H) 2.32 (s, 3 H); LCMS for C₂₂H₂₀N₂O₅S m/z 425.10 (M+H)⁺; Anal. Calcd. for C₂₂H₂₀N₂O₅S.0.65AcOH: C, 60.38; H, 4.91; N, 6.04; Found: C, 60.28; H, 4.90; N, 6.12.

Preparation of Intermediate 6a 3-Hydroxy-5-methoxy-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl iodide (6.44 mL, 104 mmol), K₂CO₃ (28.8 g, 208.15 mmol), and methyl 3,5-dihydroxybenzoate (17.5 g, 64 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.51 g, 40% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.16 (dd, J=4.80, 2.27 Hz, 2 H) 6.63 (t, J=2.27 Hz, 1 H) 5.36 (s, 1H) 3.92 (s, 3 H) 3.83 (s, 3 H).

Preparation of Intermediate 6b 3-(2,2-Diethoxy-ethoxy)-5-methoxy-benzoic acid methyl ester

To a suspension of sodium hydride (708 mg, 17.7 mmol, 60% in mineral oil) in anhydrous DMF (10 mL) was added methyl 3-hydroxy-5-methoxy benzoate (6a) (2.15 g, 11.8 mmol) at 0° C. After hydrogen evolution had ceased, bromoacetaldehyde diethyl acetal (2.22 mL, 14.75 mmol) was added. The reaction mixture was heated to 160° C. overnight. The mixture was poured into ice/water, extracted with EtOAc (2×80 mL), dried over MgSO₄, and concentrated. Purification by column chromatography (10% EtOAc in hexanes) afforded pale yellow oil (1.95 g, 55% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.23 (m, 2 H) 6.66-6.71 (m, 1 H) 4.80-4.86 (m, 1 H) 4.03 (dd, J=5.05, 1.52 Hz, 2 H) 3.91 (s, 3 H) 3.82 (s, 3 H) 3.73-3.80 (m, 2 H) 3.59-3.69 (m, 2 H) 1.21-1.28 (m, 6 H); LCMS for C₁₅H₂₂O₆ m/z 299.10 (M+H)⁺.

Preparation of Intermediate 6c 6-Methoxy-benzofuran-4-carboxylic acid methyl ester

3-(2,2-Diethoxy-ethoxy)-5-methoxy-benzoic acid methyl ester (6b) (1.95 g, 6.53 mmol) was added to a solution of polyphosphoric acid (1.47 g) in benzene (10 mL). The reaction mixture was heated to reflux for 2 hr, filtered and concentrated. The residue was purified by flash column chromatography (5% EtOAc in hexanes) to give a pale yellow solid (840 mg, 62% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J=2.27 Hz, 1 H) 7.61 (d, J=2.27 Hz, 1 H) 7.26 (d, J=2.02 Hz, 1 H) 7.25 (d, J=2.27 Hz, 1 H) 3.99 (s, 3 H) 3.90 (s, 3 H).

Preparation of Intermediate 6d 6-Hydroxy-benzofuran-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1e, from 2,6-lutidine (1.42 mL, 12.2 mmol), BBr₃ (12.2 mL, 12.2 mmol, 1.0 M in CH₂Cl₂) and 6-methoxy-benzofuran-4-carboxylic acid methyl ester (6c) (840 mg, 4.07 mmol). Purification by flash column chromatography (10-15% EtOAc in hexanes) gave a pale yellow solid (350 mg, 45% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J=2.27 Hz, 1 H) 7.61 (d, J=2.02 Hz, 1 H) 7.24 (dd, J=3.28, 2.27 Hz, 2 H) 5.66 (s, 1 H) 4.00 (s, 3 H).

Preparation of Intermediate 6e 6-Hydroxy-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester

To a solution of 6-hydroxy-benzofuran-4-carboxylic acid methyl ester (6d) (354 mg, 1.82 mmol) in EtOAc was added acetic acid (1 mL) and Pd on carbon (40 mg). The reaction mixture was stirred under hydrogen gas balloon overnight. The mixture was filtered through Celite and concentrated to give a pale yellow solid which was used without further purification. LCMS and NMR showed it was a mixture of 6-hydroxy-benzofuran-4-carboxylic acid methyl ester and 6-hydroxy-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (2:1). ¹H NMR (400 MHz, CDCl₃) δ 7.02 (d, J=2.27 Hz, 2 H) 6.53 (d, J=2.27 Hz, 1 H) 4.61 (t, J=8.72 Hz, 2 H) 3.90 (s, 3 H) 3.44 (t, J=8.72 Hz, 2 H).

Preparation of Intermediate 6f Mixture of 6-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester and 6-(4-methanesulfonyl-phenoxy)-benzo-furan-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (269 mg, 1.55 mmol), Cs₂CO₃ (1.01 g, 3.01 mmol), and a mixture of 6-hydroxy-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester (6e) and 6-hydroxy-benzofuran-4-carboxylic acid methyl ester (6d) (2:1 mixture, 300 mg, 1.55 mmol). Purification by column chromatography eluting with 30% EtOAc in hexanes gave a pale yellow solid (230 mg, 79% yield) as a mixture of 6-(4-methanesulfonyl-phenoxy)-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester and 6-(4-methanesulfonyl-phenoxy)-benzofuran-4-carboxylic acid methyl ester (1.4:1). ¹H NMR (400 MHz, CDCl₃) δ 7.87-7.94 (m) 7.76 (dd, J=14.53, 2.15 Hz) 7.44-7.53 (m) 7.39 (d, J=1.52 Hz) 7.18-7.22 (m) 7.07-7.13 (m) 6.67-6.72 (m) 4.69 (t, J=8.84 Hz) 3.95-4.01 (m) 3.87-3.92 (m) 3.56 (t, J=8.84 Hz) 3.05-3.09 (m).

Example 7 6-(4-Methanesulfonyl-phenoxy)-benzofuran-4-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from a mixtures of 6-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester and 6-(4-methanesulfonyl-phenoxy)-benzofuran-4-carboxylic acid methyl ester (6f). Purification by reverse phase chromatography gave 6-(4-methanesulfonyl-phenoxy)-benzofuran-4-carboxylic acid(5-methyl-pyridin-2-yl)-amide (21 mg, 6% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1 H) 8.33 (d, J=8.34 Hz, 1 H) 8.09 (s, 1 H) 7.93 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.80 (d, J=2.27 Hz, 1H) 7.64 (dd, J=8.59, 2.27 Hz, 1 H) 7.57 (d, J=2.02 Hz, 1 H) 7.44-7.47 (m, 1 H) 7.35-7.42 (m, 1 H) 7.12-7.17 (m, 2 H) 3.08 (s, 3 H) 2.34 (s, 3 H); LCMS for C₂₂H₁₈N₂O₅S m/z 423.10 (M+H)⁺; Anal. Calcd. for C₂₂H₁₈N₂O₅S.1.0 AcOH: C, 59.62; H, 4.54; N, 5.93; Found: C, 59.62; H, 4.54; N, 5.93.

Example 8 4-(4-Methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzo-furan-6-carboxylic acid ethyl ester (8c) (130 mg, 0.36 mmol). Purification by flash column chromatography gave a white solid (105 mg, 69% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1 H) 8.22 (d, J=8.34 Hz, 1 H) 8.11 (d, J=2.02 Hz, 1 H) 7.91-7.96 (m, 2 H) 7.57 (dd, J=8.46, 2.15 Hz, 1H) 7.19 (d, J=1.26 Hz, 1H) 7.10-7.14 (m, 3 H) 4.70 (t, J=8.84 Hz, 2 H) 3.14 (t, J=8.84 Hz, 2 H) 3.09 (s, 3 H) 2.32 (s, 3 H); LCMS for C₂₂H₂₀N₂O₅S m/z 425.10 (M+H⁺); Anal. Calcd. for C₂₂H₂₀N₂O₅S.0.10 H₂O: C, 62.09; H, 4.84; N, 6.47; Found: C, 62.02; H, 4.84; N, 6.47.

Preparation of Intermediate 8a 4-Hydroxy-benzofuran-6-carboxylic acid ethyl ester

t-Butoxide (1.7 g, 15 mmol) was added to a solution of 2-furaldehyde (2.5 mL, 30.2 mmol) and diethyl succinate (3.2 mL, 19 mmol) in t-butanol (20 mL). The mixture was refluxed for 2 hr, cooled to room temperature and acidified with aqueous HCl (20% v/v) to Ph ˜2. The mixture was diluted with 5% HCl (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were then extracted with 10% aqueous solution of Na₂CO₃ (2×100 mL). The aqueous solution was washed with EtOAc and then acidified with 20% HCl to Ph ˜2. The aqueous layer was finally extracted with EtOAc (3×100 mL), dried over MgSO₄ and concentrated to give a brown oil. The crude product was dissolved in Ac₂O (10 mL) and added NaOAc (1.6 g, 19 mmol). The mixture was heated to reflux for 5 hr, cooled to room temperature and concentrated. The residue was taken into ½ saturated Na₂CO₃, extracted with EtOAc (2×150 mL), dried over MgSO₄ and concentrated to give a brown color solid. The solid was then dissolved in EtOH (10 mL). To the solution was added K₂CO₃ (2.5 g, 18 mmol). The resulting reaction mixture was heated to reflux overnight and the solvent was removed in vacuo. The brown residue was then treated with H₂O (50 mL) and acidified with 6N HCl to pH 6. The solution was then extracted with EtOAc (2×50 mL), and combined organic layers were dried over MgSO4 and concentrated. The crude material was purified by flash column chromatography to give a yellow color solid (532 mg, 9% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1 H) 7.68 (d, J=2.02 Hz, 1 H) 7.51 (s, 1 H) 6.92-7.00 (m, 1 H) 4.42 (q, J=7.24 Hz, 2 H) 1.42 (t, J=7.20 Hz, 3 H).

Preparation of Intermediate 8b 4-Hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid ethyl ester

Pd on carbon (100 mg) was added to a solution of 4-hydroxy-benzofuran-6-carboxylic acid ethyl ester (8a) (333 mg, 1.61 mmol) in acetic acid. The mixture was stirred under H₂ (50 psi) for 48 hr. The mixture was filtered through Celite and concentrated. The residue was taken into saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 15% EtOAc in hexanes to give a pale yellow solid (315 mg, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.16 (d, J=1.26 Hz, 1 H) 7.05 (s, 1 H) 4.65 (t, J=8.72 Hz, 2 H) 4.35 (q, J=7.07 Hz, 2 H) 3.21 (t, J=8.72 Hz, 2 H) 1.38 (t, J=7.07 Hz, 3 H); LCMS for C₁₁H₁₂O₄ m/z 209.10 (M+H)⁺.

Preparation of Intermediate 8c 4-(4-Methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid ethyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (285 mg, 1.64 mmol), Cs₂CO₃ (997 mg, 3.06 mmol), and 4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid ethyl ester (8b) (315 mg, 1.51 mmol). Purification by column chromatography eluting with 10-20% EtOAC in hexanes gave a pale yellow oil (199 mg, 36% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.90-7.97 (m, 2 H) 7.34 (d, J=4.29 Hz, 1 H) 7.24-7.29 (m, 1 H) 7.07-7.13 (m, 2 H) 4.67 (m, 2 H) 4.32-4.39 (m, 2 H) 3.09-3.14 (m, 2 H) 3.06-3.09 (m, 3 H) 1.34-1.42 (m, 3 H); LCMS for C₁₈H₁₈O₆S m/z 385.00 (M+Na)⁺.

Example 9 4-(4-Methanesulfonyl-phenoxy)-benzofuran-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(4-methanesulfonyl-phenoxy)-benzofuran-6-carboxylic acid ethyl ester (9a) (153 mg, 0.43 mmol). Purification by flash column chromatography eluting with 15-20% EtOAc in hexanes gave a white solid (100 mg, 50% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H) 8.11 (s, 1 H) 7.99 (s, 1 H) 7.94 (d, J=7.58 Hz, 2 H) 7.75 (s, 1 H) 7.59 (d, J=8.34 Hz, 1 H) 7.52 (s, 1 H) 7.16 (d, J=7.33 Hz, 2 H) 6.69 (s, 1 H) 3.09 (s, 3 H) 2.32 (s, 3 H); LCMS for C₂₂H₁₈N₂O₅S m/z 423.00 (M+H)⁺; Anal. Calcd. for C₂₂H₁₈N₂O₅S.0.35 EtOAc: C, 62.00; H, 4.63; N, 6.18; Found: C, 61.70; H, 4.56; N, 6.18.

Preparation of Intermediate 9a 4-(4-Methanesulfonyl-phenoxy)-benzofuran-6-carboxylic acid ethyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (180 mg, 1.03 mmol), Cs₂CO₃ (630 mg, 1.93 mmol), and 4-hydroxy-benzofuran-6-carboxylic acid ethyl ester (8a) (199 mg, 0.97 mmol). Purification by flash column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow oil (261 mg, 75% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1 H) 7.91 (s, 2 H) 7.74 (s, 1 H) 7.65 (s, 1 H) 7.13 (s, 2 H) 6.66 (s, 1 H) 4.41 (s, 2 H) 3.08 (s, 3 H) 1.42 (s, 3 H); LCMS for C₁₈H₁₆0₆S m/z 383.00 (M+Na)⁺.

Example 10 4-(4-Methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (10d) (65 mg, 0.18 mmol). Purification by flash column chromatography eluting with 15-25% EtOAc in hexanes gave a white solid (34 mg, 43% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H) 8.22 (d, J=8.34 Hz, 1 H) 8.12 (s, 1 H) 7.93 (d, J=8.84 Hz, 2 H) 7.57 (dd, J=8.21, 1.64 Hz, 1 H) 7.14 (d, J=10.86 Hz, 2 H) 7.10 (s, 2 H) 5.01-5.10 (m, 1 H) 3.23 (dd, J=16.42, 8.84 Hz, 1 H) 3.09 (s, 3 H) 2.72 (dd, J=16.42, 7.33 Hz, 1 H) 2.32 (s, 3 H) 1.50 (d, J=6.06 Hz, 3 H); LCMS for C₂₃H₂₂N₂O₅S m/z 439.10 (M+H⁺); Anal. Calcd. for C₂₃H₂₂N₂O₅S.0.70 H2O: C, 61.24; H, 5.23; N, 6.21; Found: C, 61.21; H, 5.19; N, 6.14.

Preparation of Intermediate 10a 4-Allyl-3,5-bis-methoxymethoxy-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 3i, from 4-bromo-3,5-bis-methoxymethoxy-benzoic acid methyl ester (3 h) (0.93 g, 2.78 mmol), CsF (0.84 g, 5.53 mmol), CuI (50.0 mg, 0.26 mmol), PdCl₂ (50.0 mg, 0.28 mmol), allyltributyltin (1.10 mL, 3.55 mmol) and PtBu₃ (65.0 mg, 0.32 mmol). Purification by column chromatography eluting with 15-25% EtOAc in hexanes gave a yellow oil (3.6 g, which contained residue of tin byproduct). ¹H NMR (400 MHz, CDCl₃) δ 7.45 (s, 2 H) 5.74-6.23 (m, 1 H) 5.25 (s, 4 H) 4.94-5.02 (m, 2 H) 3.90 (s, 3 H) 3.49-3.50 (m, 2 H) 3.48 (s, 6 H); LCMS for C₁₅H₂₀O₆ m/z 297.10 (M+H⁺).

Preparation of Intermediate 10b 4-Allyl-3,5-dihydroxy-benzoic acid methyl ester

To a solution of 4-allyl-3,5-bis-methoxymethoxy-benzoic acid methyl ester (10a) (513 mg, 1.73 mmol) in MeOH (4 mL) was added 4N HCl (4 mL). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with H₂O (80 mL) and extracted with EtOAc (2×80 mL). The organic layers were dried over MgSO₄ and concentrated to give yellow oil which was purified by flash column chromatography eluting with 15-25% EtOAc in hexanes to give a pale yellow solid (285 mg, 79% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.20 (s, 2 H) 5.95-6.06 (m, J=5.31, 5.31 Hz, 1 H) 5.76-5.82 (m, 2 H) 5.15-5.20 (m, 1 H) 5.12-5.15 (m, 1 H) 3.90 (s, 3 H) 3.50-3.55 (m, 2 H); LCMS for C₁₁H₁₂O₄S m/z 209.10 (M+H⁺).

Preparation of Intermediate 10c 4-Hydroxy-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1d, from zirconium(IV) chloride and 4-allyl-3,5-dihydroxy-benzoic acid methyl ester (10b) (85 mg, 0.41 mmol). Purification by flash column chromatography eluting with 15-25% EtOAc in hexane gave a pale yellow solid (58 mg, 68% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.21 (m, 2 H) 5.76 (s, 1 H) 4.42-4.51 (m, 1H) 3.91 (s, 3 H) 3.11-3.21 (m, 2 H) 1.60 (d, J=6.57 Hz, 3 H).

Preparation of Intermediate 10d 4-(4-Methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (10c) (58 mg, 0.29 mmol). Purification by column chromatography eluting with 15-25% EtOAc in hexanes gave a pale yellow solid (65 mg, 64% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.90-7.93 (m, 2 H) 7.23-7.26 (m, 2 H) 7.10 (s, 1 H) 7.07 (s, 1 H) 4.98-5.07 (m, 1 H) 3.89 (s, 3 H) 3.21 (dd, J=16.67, 8.84 Hz, 1 H) 3.07 (s, 3 H) 2.70 (dd, J=16.55, 7.45 Hz, 1 H) 1.48 (d, J=6.32 Hz, 3 H); LCMS for C₁₈H₁₈O₆S m/z 385.10 (M+Na)⁺.

Example 11 4-(4-Methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (10d). ¹H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1 H) 7.93 (d, J=8.84 Hz, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 7.12 (d, J=8.84 Hz, 2 H) 7.10 (s, 1 H) 7.06 (s, 1 H) 6.78 (d, J=2.27 Hz, 1 H) 5.01-5.09 (m, 1 H) 3.82 (s, 3 H) 3.24 (dd, J=16.42, 8.84 Hz, 1 H) 3.09 (s, 3 H) 2.73 (dd, J=16.29, 7.45 Hz, 1 H) 1.49 (d, J=6.32 Hz, 3 H); LCMS for C₂₁H₂₁N₃O₅S m/z 428.10 (M+H)⁺; Anal. Calcd. for C₂₁H₂₁N₃O₅S.0.23 H₂O: C, 58.44; H, 5.01; N, 9.74; Found: C, 58.43; H, 4.92; N, 9.68.

Example 12 (−)-4-(4-Methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide and Example 13 (+)4-(4-Methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl -1H-pyrazol-3-yl)-amide

The title compounds were prepared from chiral column chromatography of Example 11.

Example 12: [α]_(D)=−21.49; 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1 H) 7.90-8.01 (m, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 7.11 (d, J=8.59 Hz, 2 H) 7.10 (s, 1 H) 7.06 (s, 1 H) 6.78 (d, J=2.27 Hz, 1 H) 5.00-5.12 (m, 1 H) 3.81 (s, 3 H) 3.24 (dd, J=16.42, 8.84 Hz, 1 H) 3.09 (s, 3 H) 2.73 (dd, J=16.29, 7.45 Hz, 1 H) 1.49 (d, J=6.32 Hz, 3 H); LCMS for C₂₁H₂₁N₃O₅S m/z 428.10 (M+H)⁺; Anal. Calcd. for C₂₁ H₂₁ N₃O₅S: C, 59.00; H, 4.95; N, 9.83; Found: C, 58.82; H, 4.96; N, 9.70.

Example 13: [α]_(D)=+19.13; 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H) 7.92 (d, J=8.84 Hz, 2 H) 7.29 (d, J=2.02 Hz, 1 H) 7.11 (d, J=8.59 Hz, 2 H) 7.10 (s, 1 H) 7.06 (s, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 5.00-5.12 (m, 1 H) 3.81 (s, 3 H) 3.23 (dd, J=16.42, 8.84 Hz, 1 H) 3.09 (s, 3 H) 2.72 (dd, J=16.42, 7.58 Hz, 1 H) 1.49 (d, J=6.32 Hz, 3 H); LCMS for C₂₁H₂₁N₃O₅S m/z 428.10 (M+H)⁺; Anal. Calcd. for C₂₁H₂₁N₃O₅S.0.23 H₂O: C, 58.44; H, 5.01; N, 9.74; Found: C, 58.44; H, 4.99; N, 9.68.

Example 14 6-[(4-Isobutoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-nicotinic acid

To a solution of 6-[(4-isobutoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-nicotinic acid methyl ester (14b) (125 mg, 0.31 mmol) in THF (4 mL) was added 1 N aqueous NaOH (300 uL, 0.3 mmol). The mixture was stirred at room temperature overnight, diluted with H₂O (15 mL) and washed with EtOAc (15 mL). The water phase was acidified with 1 N HCl to Ph ˜5, extracted with CH₂Cl₂ (2×15 mL), dried over MgSO₄ and concentrated to give a white solid (36 mg, 30% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (br. s., 1 H) 11.04 (s, 1 H) 8.88 (s, 1 H) 8.28-8.35 (m, 2 H) 7.20 (s, 1 H) 6.98 (s, 1 H) 3.88 (d, J=6.57 Hz, 2 H) 2.96 (s, 2 H) 1.99-2.09 (m, 1 H) 1.43 (s, 6 H) 1.00 (d, J=6.57 Hz, 6 H); LCMS for C₂₁H₂₄N₂O₅ m/z 385.10 (M+H⁺); Anal. Calcd. for C₂₁H₂₄N₂O₅.0.10 EtOAc: C, 65.36; H, 6.36; N, 7.12; Found: C, 65.26; H, 6.21; N, 6.91.

Preparation of Intermediate 14a 4-Isobutoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid methyl ester

To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (167 mg, 0.75 mmol) in DMF (3 mL) was added 1-bromo-2-methylpropane (0.090 mL, 0.83 mmol) and cesium carbonate (520 mg, 1.6 mmol). The reaction mixture was stirred at 85° C. for 2 hr and cooled to room temperature. The mixture was quenched with H₂O (10 mL), extracted with EtOAc (2×10 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexanes to give colorless oil (193 mg, 92% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.09 (s, 1 H) 7.05 (s, 1 H) 3.89 (s, 3 H) 3.80 (d, J=6.57 Hz, 2 H) 2.99 (s, 2 H) 2.02-2.16 (m, 1 H) 1.49 (s, 6 H) 1.04 (s, 3 H) 1.02 (s, 3 H); LCMS for C₁₆H₂₂O₄ m/z 279.10 (M+H⁺).

Preparation of Intermediate 14b 6-[(4-Isobutoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-nicotinic acid methyl ester

The title compound was prepared in a similar manner as described for Example 1, from 6-aminonicotinic acid methyl ester (1.0 g, 6.57 mmol) and 4-isobutoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (14a) (185 mg, 0.66 mmol). Purification by column chromatography eluting with 15-25% EtOAc in hexane gave a pale yellow solid (127 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, J=1.52 Hz, 1 H) 8.69 (s, 1 H) 8.42-8.48 (m, 1 H) 8.35 (dd, J=8.72, 2.15 Hz, 1 H) 6.96 (s, 1 H) 6.87 (s, 1H) 3.95 (s, 3 H) 3.82 (d, J=6.32 Hz, 2 H) 3.01 (s, 2 H) 2.06-2.14 (m, J=13.33, 6.60, 6.60 Hz, 1 H) 1.51 (s, 6 H) 1.04 (d, J=6.82 Hz, 6 H); LCMS for C₂₂H₂₆N₂O₅ m/z 399.10 (M+H⁺).

Example 15 6-{[4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl]-amino}-nicotinamide

To a solution of 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (15a) (77 mg, 0.21 mmol) in DMF (3 mL) was added Et₃N (90.0 uL, 0.65 mmol), 4-aminonicotinic amide (60.0 mg, 0.44 mmol) and HATU (250 mg, 0.66 mmol). The mixture was stirred at room temperature for 3 hr. The mixture was quenched with H₂O (10 mL), extracted with EtOAc (2×10 mL). The organic layers was washed with H₂O (2×20 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 15-30% EtOAc in hexanes to give colorless oil (39 mg, 38% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.74 (dd, J=4.42, 1.39 Hz, 1 H) 8.46 (dd, J=8.34, 1.26 Hz, 1 H) 7.96 (d, J=8.84 Hz, 2 H) 7.52 (s, 1 H) 7.42-7.50 (m, 2 H) 7.15 (d, J=8.84 Hz, 2 H) 3.08 (s, 3 H) 2.99 (s, 2 H) 1.54 (s, 6 H); LCMS for C₂₄H₂₃N₃O₆S m/z 482.00 (M+H)⁺.

Preparation of Intermediate 15a 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid

To a solution of 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3f) (76 mg, 0.20 mmol) in MeOH (5 mL) was added 3N aqueous NaOH (0.20 mL, 0.60 mmol). The mixture was heated to 60° C. overnight, and concentrated. The residue was diluted with H₂O (10 mL) extracted with EtOAc (10 mL). The water phase was acidified with 1N HCl to Ph ˜1, extracted with CH₂Cl₂ (2×10 mL). The organic layers were dried over MgSO₄ and concentrated to give an off-white solid (77 mg, 100% yield). LCMS for C₂₄H₂₃N₃O₆S m/z 385.00 (M+Na)⁺.

Examples 16-21 were prepared in a similar manner as described for Example 1, from 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3f) and the appropriate amino heterocycles.

Example 16 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 17 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxy-lic acid pyrazin-2-ylamide

Example 18 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(4-methoxy-pyridin-2-yl)-amide

Example 19 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid pyridin-2-ylamide

Example 20 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 21 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (6-methyl-pyridazin-3-yl)-amide

Example MW MF NMR m/z Elemental Analysis 16 441.5 C22H23N3O5S ¹H NMR (400 MHz, CDCl₃)) δ 8.55 (s, 1 H) 442.10 (M + H⁺) Calcd. for C₂₂H₂₃N₃O₅S•0.07 7.91 (d, J = 8.34 Hz, 2 H) 7.07 (dd, EtOAc: C, 59.78; H, J = 16.67, 8.34 Hz, 4 H) 6.78 (s, 1 H) 5.30; N, 9.39; Found: C, 3.78 (s, 3 H) 3.08 (s, 3 H) 2.90 (s, 2 H) 1.50 (s, 59.78; H, 5.24; N, 9.28 6 H); 17 439.5 C22H21N3O5S ¹H NMR (400 MHz, CDCl₃)) δ 9.66 (s, 1 440.10 (M + H⁺) Calcd. for C₂₂H₂₁N₃O₅S•0.20 H) 8.41 (d, J = 13.64 Hz, 2 H) 8.27 (s, 1 H) H₂O: C, 59.64; H, 4.87; 7.93 (d, J = 8.59 Hz, 2 H) 7.09-7.18 (m, 4 N, 9.48; Found: C, 59.72; H, H) 3.09 (s, 3 H) 2.92 (s, 2 H) 1.51 (s, 6 H); 5.07; N, 9.47 18 468.5 C24H24N2O6S ¹H NMR (400 MHz, CDCl₃)) δ 8.56 (s, 1 H) 469.10 (M + H⁺) Calcd. for C₂₄H₂₄N₂O₆S•0.10 8.05 (d, J = 4.80 Hz, 1 H) 7.95 (d, J = 14.91 Hz, H₂O: C, 61.29; H, 5.19; 2 H) 7.91 (s, 1 H) 7.07-7.18 (m, 4 H) N, 5.96; Found: C, 61.24; H, 6.63 (s, 1 H) 3.90 (s, 3 H) 3.08 (s, 3 H) 5.24; N, 6.05. 2.91 (s, 2 H) 1.51 (s, 6 H); 19 438.5 C23H22N2O5S ¹H NMR (400 MHz, CDCl₃)) δ 8.56 (s, 1 H) 439.10 (M + H⁺) Calcd. for C₂₃H₂₂N₂O₅S•0.30 8.34 (d, J = 8.59 Hz, 1 H) 8.30 (d, J = 4.04 Hz, H₂O: C, 62.23; H, 5.13; 1 H) 7.89-7.97 (m, 2 H) N, 6.31; Found: C, 62.18; H, 7.72-7.83 (m, 1 H) 7.16 (s, 1 H) 7.07-7.14 5.19; N, 6.14. (m, 4 H) 3.09 (s, 3 H) 2.91 (s, 2 H) 1.51 (s, 6 H); 20 442.5 C21H22N4O5S ¹H NMR (400 MHz, CDCl₃)) δ 8.31 (s, 1 H) 443.10 (M + H⁺) Calcd. for C₂₁H₂₂N₄O₅S•0.55 8.08 (s, 1 H) 7.93 (d, J = 8.84 Hz, 2 H) H₂O: C, 55.75; H, 5.15; 7.11 (d, J = 8.84 Hz, 2 H) 7.07 (d, J = 1.26 Hz, 2 N, 12.38; Found: C, 55.89; H) 4.14 (s, 3 H) 3.09 (s, 3 H) 2.92 (s, 2 H) H, 5.09; N, 12.20. 1.51 (s, 6 H); 21 453.5 C23H23N3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1 H) 454.10 (M + H)⁺ 8.46 (d, J = 9.09 Hz, 1 H) 7.94 (d, J = 8.59 Hz, 2 H) 7.39 (d, J = 9.09 Hz, 1 H) 7.18 (s, 1 H) 7.11-7.15 (m, 2 H) 7.11 (s, 1 H) 3.09 (s, 3 H) 2.92 (s, 2 H) 2.68 (s, 3 H) 1.52 (s, 6 H);

Example 22 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-hydroxymethyl-pyridin-2-yl)-amide

To a solution of 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-amide (22b) (85 mg, 0.15 mmol) in CH₂Cl₂ (5 mL) was added TBAF in THF (220 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H₂O (20 mL), and extracted with CH₂Cl₂ (2×20 mL). The organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 50% EtOAc in hexanes to give a white solid (23 mg, 34% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1 H) 8.34 (d, J=8.34 Hz, 1 H) 8.30 (s, 1 H) 7.93 (d, J=8.84 Hz, 2 H) 7.74-7.83 (m, 1 H) 7.08-7.17 (m, 4 H) 4.72 (s, 2 H) 3.09 (s, 3 H) 2.91 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₄H₂₄N₂O₆S m/z 469.10 (M+H)⁺.

Preparation of Intermediate 22a 5-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine

A mixture of (6-aminopyridin-3-yl)methanol (1.76 g, 14.2 mmol), TBDMSCl (2.18 g, 14.5 mmol), and imidazole (2.90 g, 42.6 mmol) in 20 mL DMF was stirred at room temperature for 2 hr. H₂O was added, extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried with Na₂SO₄, and concentrated to give an off-white solid (2.57 g, 76% yield). ¹H NMR (400 MHz, CDCl₃)) δ 8.01 (d, J=1.77 Hz, 1 H) 7.44 (dd, J=8.34, 2.27 Hz, 1 H) 6.50 (d, J=8.34 Hz, 1 H) 4.60 (s, 2 H) 4.38 (br. s., 2 H) 0.93 (s, 9H) 0.11 (s, 6 H); LCMS for C₁₂H₂₂N₂OSi m/z 239.00 (M+H).

Preparation of Intermediate 22b 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-amide

To a solution of 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (15a) (723 mg, 2.0 mmol) in DMF (5 mL) was added Et₃N (600 uL. 4.30 mmol), HATU (1.52 g, 4.00 mmol) and 5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (22a) (338 mg, 1.42 mmol). The reaction mixture was stirred at 40° C. overnight, quenched with H₂O (80 mL), and extracted with EtOAc (2×80 mL). The combined organic layers were washed with H₂O (2×100 mL), dried over MgSO₄ and concentrated to give a brown solid which was purified by flash chromatography to give an off-white solid (91 mg, 8% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1 H) 8.30 (d, J=8.59 Hz, 1 H) 8.25 (s, 1 H) 7.93 (d, J=8.84 Hz, 2 H) 7.71 (dd, J=8.59, 2.27 Hz, 1 H) 7.14 (d, J=1.26 Hz, 1 H) 7.12 (s, 1 H) 7.10 (d, J=1.77 Hz, 2 H) 4.73 (s, 2 H) 3.08 (s, 3 H) 2.91 (s, 2 H) 1.47-1.53 (m, 6 H) 0.94 (s, 9 H) 0.11 (s, 6 H); LCMS for C₃₀H₃₈N₂O₆SSi m/z 582.20 (M+H)⁺.

Examples 23 and 24 were prepared in parallel from 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl chloride (23a) and the appropriate amino heterocycles: To appropriate 20 mL vials were delivered the amine solution (1.2 mL, 0.656 mmol, 0.5M in anhydrous DMA solution, 5 equiv.) and pyridine (0.032 mL, 0.394 mmol, 3 equiv). The acid chloride stock solution (260 μL, 0.13 mmol, 1 equiv, 0.5M in anhydrous acetonitrile solution) was delivered to each vial. The reaction vials were transferred to a heating block that had been preheated to 50° C. and stirred for 8 h at that temperature. Then the reaction mixtures were concentrated in vacuo at 35-40° C. to remove volatiles. The dried residues were dissolved DCM for further analysis and purification by flash chromatography. Fractions were collected in pre-tared tubes and lyophilized to dryness.

Example 23 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(4-methyl-pyridin-2-yl)-amide

Yield: 10 mg (17%). LC-MS 453 (M+H)⁺, ¹H NMR (400 MHz, ACETONITRILE-d₃) δ 1.46 (s, 6 H) 2.36 (s, 3H) 2.87 (s, 2 H) 3.05 (s, 3 H) 6.94 (s, J=4.53 Hz, 1 H) 7.07-7.23 (m, 4 H) 7.89 (d, J=8.81 Hz, 2H) 8.10 (2, 2 H).

Preparation of Intermediate 23a 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl chloride

4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (15a) (3.35 g, 9.24 mmol) was dissolved in SOCl₂ (50 mL) and DCM (20 mL) and stirred at room temperature for 2 hr. The volatiles were removed to give 3.3 g of a yellow solid (94% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.51 (s, 6 H) 2.91 (s, 2 H) 3.06 (s, 3 H) 7.10 (d, J=8.56 Hz, 2 H) 7.30 (s, 1 H) 7.35 (s, 1 H) 7.93 (d, J=8.56 Hz, 2 H).

Example 24 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(5-methyl-[1,3,4]thiadiazol-2-yl)-amide

Yield: 10 mg (17%). LCMS 460 (M+H)⁺, ¹H NMR (400 MHz, ACETONITRILE-d₃) δ 1.46 (s, 6 H) 2.63 (s, 3H) 2.90 (s, 2 H) 3.06 (s, 3 H) 7.17 (d, J=8 Hz, 2 H) 7.23 (s, 2 H) 7.91 (d, J=12 Hz, 2H) 10.47 (s, 1H).

Examples 25-30 were prepared in parallel from 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl chloride (23a) and the appropriate amino heterocycles: To appropriate test tubes were delivered the amine stock solution (700 μL, 0.35 mmol, 0.5M in anhydrous DMA solution, 5 equiv.) and 2.5 M pyridine in DMA (84 μL, 0.21 mmol, 3 equiv). The acid chloride stock solution (200 μL, 0.07 mmol, 1 equiv, 0.5M in anhydrous acetonitrile solution) was delivered to each test tube. The tubes were transferred from the rack to a reactor block that had been preheated to 50° C. and stirred for 8 h at that temperature. Then the reaction mixtures were concentrated in vacuo at 35-40° C. to remove volatiles. The dried residues were dissolved in DMSO for further analysis and purification by preparative HPLC. Fractions were collected in pre-tared tubes and lyophilized to dryness.

Example 25 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(5-methyl-isoxazol-3-yl)-amide

Example 26 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid isoxazol-3-ylamide

Example 27 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(5-ethyl-[1,3,4]thiadiazol-2-yl)-amide

Example 28 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide

Example 29 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(2-ethyl-2H-[1,2,3]triazol-4-yl)-amide

Example 30 4-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(5-methoxymethyl-[1,3,4]thiadiazol-2-yl)-amide

Example MW MF NMR m/z 25 442.5 C22H22N2O6S ¹H NMR (500 MHz, DMSO-d6, ppm) δ 443.1 (M + H⁺) 1.37 (s, 6H), 2.32 (s, 3H), 2.60-2.85 (m, 2H), 3.12 (s, 3H), 6.61 (s, 1H), 7.10-7.20 (m, 4H), 7.83-7.90 (m, 2H). 26 428.5 C21H20N2O6S ¹H NMR (500 MHz, DMSO-d6, ppm) δ 429.1 (M + H⁺) 1.38 (s, 6H), 2.85 (s, 2H), 3.14 (s, 3H), 6.90-6.95 (m, 1H), 7.15-7.21 (m, 4H), 7.85-7.90 (m, 2H), 8.72 (s, 1H). 27 473.6 C22H23N3O5S2 ¹H NMR (500 MHz, DMSO-d6, ppm) δ 474.1 (M + H⁺) 1.23-1.28 (m, 3H), 1.39 (s, 6H), 2.84-2.88 (m, 2H), 2.90-2.97 (m, 2H), 3.13 (s, 3H), 7.15-7.20 (m, 2H), 7.25-7.30 (m, 2H), 7.86-7.91 (m, 2H). 28 485.6 C23H23N3O5S2 ¹H NMR (500 MHz, DMSO-d6, ppm) δ 486.1 (M + H⁺) 0.9-0.95 (m, 2H), 1.07-1.15 (m, 2H), 1.34-1.41 (s, 7H), 2.84-2.88 (m, 2H), 3.13 (s, 3H), 7.15-7.20 (m, 2H), 7.24-7.28 (m, 2H), 7.86-7.91 (m, 2H). 29 456.5 C22H24N4O5S ¹H NMR (500 MHz, DMSO-d6, ppm) δ 457.1 (M + H⁺) 1.36-1.41 (m, 9H), 2.83-2.88 (m, 2H), 3.34 (s, 3H), 4.26-4.35 (m, 2H), 7.15-7.25 (m, 4H), 7.85-7.93 (m, 2H). 30 489.6 C22H23N3O6S2 ¹H NMR (500 MHz, DMSO-d6, ppm) δ 490.1 (M + H⁺) 1.41 (s, 6H), 2.60-2.90 (m, 2H), 3.30-3.36 (m, 6H), 4.70-4.75 (m, 2H), 7.16-7.18 (m, 2H), 7.30-7.34 (m, 2H), 7.87-7.94 (m, 2H).

Example 31 4-(4-Cyano-2-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 1f, from 3,4-difluorobenzonitrile (11 mg, 0.080 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) (23 mg, 0.080 mmol) to give a colorless oil (8 mg, 20% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1 H) 7.50 (dd, J=10.11, 1.77 Hz, 1 H) 7.42 (d, J=8.59 Hz, 1 H) 7.28 (d, J=2.02 Hz, 1 H) 7.00-7.08 (m, 2 H) 6.95 (s, 1 H) 6.77 (d, J=1.77 Hz, 1 H) 3.78 (s, 3 H) 2.97 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₂H₁₉FN₄O₃ m/z (M+H)⁺407.10.

Preparation of Intermediate 31a 4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methylpyrazole (201 mg, 2.07 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (45 mg, 0.22 mmol) to give a white solid (28 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1 H) 7.30 (d, J=1.77 Hz, 1 H) 7.05-7.12 (m, 1 H) 7.00 (s, 1 H) 6.80 (d, J=2.02 Hz, 1 H) 3.81 (s, 3 H) 3.00 (s, 2 H) 1.50 (s, 6 H); LCMS for C₁₅H₁₇N₃O₃ m/z 288.10 (M+H)⁺.

Example 32 4-[4-(Azetidine-1-carbonyl)-2-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzo-furan-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methylpyrazole (250 mg, 2.57 mmol) and 4-[4-(azetidine-1-carbonyl)-2-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1 H-pyrazol-3-yl)-amide (32b) (103 mg, 0.26 mmol). Purification by reverse phase column chromatography gave a white solid (50 mg, 42% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H) 7.49-7.58 (m, 1 H) 7.40 (dd, J=8.46, 1.14 Hz, 1 H) 6.98-7.05 (m, 2 H) 6.93 (s, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 4.32-4.43 (m, 2 H) 4.21-4.32 (m, 2 H) 3.78-3.82 (m, 3 H) 2.98 (s, 2 H) 2.34-2.43 (m, 2 H) 1.51 (s, 6 H); LCMS for C₂₅H₂₅FN₄O₄ m/z 465.10 (M+H)⁺; Anal. Calcd. for C₂₅H₂₅FN₄O₄: C, 64.65; H, 5.43; N, 12.06; Found: C, 64.36; H, 5.31; N, 11.78.

Preparation of Intermediate 32a Azetidin-1-yl-(3,4-difluoro-phenyl)-methanone

3,4-Difluorobenzoic acid (1.03 g, 6.51 mmol) in CH₂Cl₂ (10 ml) was added SOCl₂ (600 uL, 8.26 mmol) and DMF (3 drop). The reaction mixture was heated to reflux for 3 hr. The mixture was evaporated under vacuum and dried. The oil/solid mixture was taken into CH₂Cl₂ (20 mL) and added azetidine hydrochloride (731 mg, 7.82 mmol) and triethylamine (2.75 mL, 19.7 mmol). The reaction mixture was stirred at room temperature for 2 hr, quenched with 1 N HCl (60 mL) and extracted with EtOAc. The organic layers were dried over MgSO₄ and concentrated to give pale yellow oil which was purified by flash column chromatography eluting with 30% EtOAc in hexanes to give a white solid (553 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.50 (m, 1 H) 7.40 (m 1 H) 7.16-7.25 (m, 1 H) 4.32 (d, J=6.82 Hz, 2 H) 4.24 (d, J=7.07 Hz, 2 H) 2.33-2.42 (m, 2 H).

Preparation of Intermediate 32b 4-[4-(Azetidine-1-carbonyl)-2-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from azetidin-1-yl-(3,4-difluoro-phenyl)-methanone (32a) (90 mg, 0.46 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (117 mg, 0.53 mmol) to give a pale yellow oil (106 mg, 59% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.51 (dd, J=10.86, 2.02 Hz, 1 H) 7.38-7.42 (m, 1 H) 7.21 (d, J=1.01 Hz, 1 H) 7.09 (d, J=1.01 Hz, 1 H) 6.99 (t, J=8.21 Hz, 1 H) 4.30-4.40 (m, 2 H) 4.20-4.29 (m, 2 H) 3.86 (s, 3 H) 2.97 (s, 2 H) 2.33-2.43 (m, 2 H) 1.50 (s, 6 H).

Example 33 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide and Example 34 4-[2-(Azetidine-1-carbonyl)-5-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) (421 mg, 1.47 mmol) and Cs₂CO₃ (965 mg, 2.96 mmol) was added to a solution of azetidin-1-yl(2,4-difluorophenyl)methanone (33a) (292 mg, 1.48 mmol). The reaction mixture was heated to 160° C. for 2 hr in a microwave. The mixture was filtered and concentrated, The residue was purified by SFC chromatography to give 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (315 mg, 46% yield) and 4-[2-(azetidine-1-carbonyl)-5-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (34 mg, 5% yield) as white solid.

Example 33: ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H) 7.50-7.57 (m, 1 H) 7.29 (d, J=2.53 Hz, 1 H) 7.05 (d, J=2.27 Hz, 2 H) 6.76-6.85 (m, 2 H) 6.67 (dd, J=11.12, 2.53 Hz, 1 H) 4.13-4.24 (m, 4 H) 3.81 (s, 3 H) 2.89 (s, 2 H) 2.30-2.39 (m, 2 H) 1.49 (s, 6 H); LCMS for C₂₅H₂₅FN₄O₄ m/z 465.20 (M+H)⁺.

Example 34: ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1 H) 7.46 (dd, J=8.46, 6.44 Hz, 1H) 7.29 (d, J=2.02 Hz, 1 H) 7.04 (d, J=2.02 Hz, 2 H) 6.87 (td, J=8.15, 2.40 Hz, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 6.58 (dd, J=9.85, 2.27 Hz, 1 H) 4.07-4.16 (m, 4 H) 3.82 (s, 3 H) 2.91 (s, 2 H) 2.23-2.33 (m, 2 H) 1.49 (s, 6 H); LCMS for C₂₅H₂₅FN₄O₄ m/z 465.20 (M+H)⁺.

Preparation of Intermediate 33a Azetidin-1-yl-(2,4-difluoro-phenyl)-methanone

To a solution of 2,4-difluorobenzoyl chloride (1.14 g, 6.46 mmol) in CH₂Cl₂ was added azetidine hydrochloride (1.46 g, 15.6 mmol) and Et₃N (2.70 mL, 19.4 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H₂O (100 mL), and extracted with CH₂Cl₂ (2×100 mL). The organic layers were dried over MgSO₄ and concentrated to give an off-white solid (896 mg, 76% yield) which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.59 (m, 1 H) 6.91-6.98 (m, 1 H) 6.81-6.87 (m, 1 H) 4.21 (t, J=7.71 Hz, 2 H) 4.11 (t, J=7.71 Hz, 2H) 2.30-2.38 (m, 2 H).

Example 35 4-[4-(Azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 15, from 4-[4-(azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (35c) (598 mg, 1.63 mmol) and 1-methyl-3-aminopyrazole (236 mg, 2.43 mmol) to give a white solid (315 mg, 41% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1 H) 7.65 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.28 (d, J=2.27 Hz, 1 H) 7.02 (dd, J=9.85, 1.26 Hz, 2 H) 6.98 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 6.78 (d, J=2.02 Hz, 1 H) 4.30-4.40 (m, 2 H) 4.19-4.30 (m, 2 H) 3.81 (s, 3 H) 2.89 (s, 2 H) 2.32-2.40 (m, 2 H) 1.49 (s, 6 H); LCMS for C₂₅H₂₆N₄O₄ m/z 447.20 (M+H)⁺; Anal. Calcd. for C₂₅H₂₆N₄O₄.0.31 H2O: C, 65.38; H, 6.02; N, 12.20; Found: C, 65.37; H, 5.85; N, 12.38.

Preparation of Intermediate 35a Azetidin-1-yl-(4-bromo-phenyl)-methanone

Et₃N (2.00 mL, 14.3 mmol) and azetidine hydrochloride (462 mg, 4.94 mmol) were added to a solution of 4-bromobenzoyl chloride (1.07 g, 4.88 mmol) in CH₂Cl₂ (20 mL). The mixture was stirred at room temperature for 2 hr, diluted with CH₂Cl₂ (100 mL), and washed with 1N aqueous HCl (100 mL), H₂O (100 mL), and brine (100 mL). The organic layer was dried over MgSO₄ and concentrated to give a colorless oil (1.10 g, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (ddd, J=17.43, 6.57, 2.27 Hz, 4 H) 4.21-4.32 (m, 4 H) 2.32-2.40 (m, 2 H);); LCMS for C₁₀H₁₀BrNO m/z 241.00 (M+H)⁺.

Preparation of Intermediate 35b 4-[4-(Azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

K₃PO₄ (1.23 g, 5.79 mmol), Pd(OAc)₂ (41 mg, 0.81 mmol) and 2-di-t-butylphosphino-2′,4′6′-tri-i-propyl-1,1′-biphenyl (68 mg, 0.16 mmol) was added to a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (646 mg, 2.91 mmol) and azetidin-1-yl-(4-bromo-phenyl)-methanone (35a) (697 mg, 2.90 mmol) in toluene (10 mL). The reaction mixture was heated to 110° C. overnight. The mixture was filtered, washed with EtOAc, and concentrated. The residue was purified by flash column chromatograph eluting with 10-25 % EtOAc in hexanes to give a white solid (802 mg, 72% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J=6.82 Hz, 2 H) 7.23 (s, 1 H) 7.20 (s, 1 H) 6.97 (d, J=7.33 Hz, 2 H) 4.24-4.34 (m, 4 H) 3.87 (s, 3 H) 2.88 (s, 2 H) 2.50-2.61 (m, 1 H) 2.32-2.42 (m, 1H) 1.47 (s, 6 H); LCMS for C₂₂H₂₃NO₅ m/z 382.00 (M+H)⁺.

Preparation of Intermediate 35c 4-[4-(Azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid

Aqueous NaOH (3 N, 2.1 mL, 6.3 mmol) was added to a solution of 4-[4-(azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (35b) (802 mg, 2.10 mmol) in 10 mL CH₃OH. The mixture was heated to 60° C. for 3 hr, concentrated, diluted with H₂O (60 mL) and acidified with 1N aqueous HCl to Ph ˜1. The aqueous phase was extracted with CH₂Cl₂ (60 mL), dried with MgSO₄ and concentrated to give a white solid (598 mg, 74% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1 H) 7.67 (d, J=7.33 Hz, 2 H) 7.02-7.10 (m, 3 H) 6.99 (s, 1 H) 4.32 (s, 2 H) 4.03 (s, 2 H) 2.89 (s, 2 H) 2.21-2.30 (m, 2 H) 1.42 (s, 6 H); LCMS for C₂₁H₂₁NO₅ m/z 468.00 (M+H)⁺.

Example 36 4-(3-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) (117 mg, 0.41 mmol) in CH₂Cl₂ (5 mL) was added (3-methylsulfonyl)boronic acid (163 mg, 0.814 mmol), Cu(OAc)₂ (74 mg, 2.04 mmol), 4A Molecular Sieves (500 mg) and Et₃N (0.300 mL, 2.15 mmol). The reaction mixture was stirred at room temperature overnight. LCMS showed about 50% conversion. More (3-methylsulfonyl)boronic acid (81 mg) was added, and the mixture was stirred at room temperature for 48 hrs, filtered, and concentrated. The residue was purified by flash column chromatograph eluting with 20-60% EtOAc in hexanes to give a white solid (57 mg, 32% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.62-10.73 (m, 1 H) 8.20 (s, 1 H) 8.02 (d, J=8.59 Hz, 1 H) 7.88-7.97 (m, 2 H) 7.64 (d, J=8.59 Hz, 1 H) 7.40 (d, J=1.26 Hz, 1 H) 7.27-7.36 (m, 1 H) 7.12-7.25 (m, 2 H) 4.85-4.99 (m, 1 H) 3.87-4.19 (m, 2 H) 3.20 (s, 3 H) 2.80 (dd, J=16.93, 4.29 Hz, 1 H) 2.48-2.60 (m, 1 H) 2.46-2.56 (m, 2 H) 2.27 (s, 3 H); LCMS for C₂₂H₂₃N₃O₅S m/z 442.00 (M+H)⁺; Anal. Calcd. for C₂₂H₂₃N₃O₅S.0.28 H₂O: C, 59.17; H, 5.32; N, 9.41; Found: C, 59.18; H, 5.31; N, 9.32.

Example 37 4-[3-(Azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Al(CH₃)₂Cl (4.85 mL, 1.85 mmol, 1.0M solution in hexane) was added to a solution of azetidine hydrochloride (173 mg, 1.85 mmol) in 1,2-dichloroethane (5 mL) at 0° C. The mixture was stirred at room temperature for 15 min, and then added 3-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-benzoic acid methyl ester (37a) (78 mg, 0.19 mmol) in 1,2-dichloroethane (2 mL). The resulting mixture was stirred at room temperature overnight. LCMS show about 30% conversion. The mixture was heated to 60° C. overnight. The reaction mixture was quenched with 20% potassium sodium tartrate tetrahydrate (5 mL) and diluted with H₂O (30 mL). The resulted suspension was extracted with CHCl₃ (2×30 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 50-70% EtOAc in hexanes to give a white solid (42 mg, 51% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1 H) 7.33-7.43 (m, 3 H) 7.10 (dd, J=7.45, 1.89 Hz, 1H) 7.01 (s, 1 H) 6.96 (s, 1 H) 6.76 (d, J=2.27 Hz, 1 H) 4.30 (t, J=7.45 Hz, 2 H) 4.22 (t, J=7.71 Hz, 2 H) 3.80 (s, 3H) 2.94 (s, 2 H) 2.30-2.41 (m, 2 H) 1.50 (s, 6 H); LCMS for C₂₅H₂₆N₄O₄ m/z 447.20 (M+H)⁺; Anal. Calcd. for C₂₅H₂₆N₄O₄.0.50 H₂O.0.10 EtOAc: C, 65.70; H, 6.03; N, 12.07; Found: C, 65.80; H, 5.87; N, 11.85.

Preparation of Intermediate 37a 3-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-benzoic acid methyl ester

A flask is charged with 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (233 mg, 0.811 mmol), Cu(OAc)₂ (147 mg, 0.811 mmol), (3-methoxy-carbonylphenol)boronic acid (438 mg, 2.43 mmol), and powdered 4A molecular sieves (500 mg). CH₂Cl₂ (8 mL) was added to yield a solution, followed by Et₃N (0.56 mL, 4.02 mmol). The reaction mixture was stirred at room temperature overnight. Additional boronic acid (146 mg, 0.811 mmol) was added. The mixture was stirred at room temperature for 2 days, filtered, washes with EtOAc. The filtrated was concentrated. The residue was purified by flash column chromatograph eluting with 60-80% EtOAc in hexanes to give a white solid (79 mg, 23% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1 H) 7.81 (d, J=6.82 Hz, 1 H) 7.65 (s, 1 H) 7.42 (t, J=7.96 Hz, 1H) 7.22 (dd, J=8.08, 2.53 Hz, 1 H) 7.09 (s, 1 H) 7.01 (s, 1 H) 6.81 (d, J=2.02 Hz, 1 H) 3.87-3.97 (m, 4 H) 3.80 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H). LCMS for C₂₃H₂₃N₃O₅ m/z 422.20 (M+H)⁺.

Example 38 4-(4-Difluoromethyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

A mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (102 mg, 0.36 mmol), 1-bromo-4-difluoromethyl benzene (110 mg, 0.53 mmol), Cs₂CO₃ (174 mg, 0.53 mmol) and CuI (1 mg) in DMF (5 mL) was heated for 2 hr at 160° C. in the microwave. The mixture was filtered and the filtrate was purified by reverse phase chromatograph to give a white solid (18 mg, 12% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.92 (d, J=2.02 Hz, 1 H) 8.52 (s, 1 H) 7.72 (dd, J=10.36, 1.77 Hz, 1 H) 7.64 (d, J=8.34 Hz, 1 H) 7.28 (s, 1 H) 7.09 (t, J=7.96 Hz, 1 H) 7.05 (s, 1 H) 6.97 (s, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 3.78 (s, 3 H) 2.98 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₂H₂₁F₂N₃O₃ m/z 414.00 (M+H)⁺.

Example 39 4-(4-Dimethylaminomethyl-2-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide and Example 40 4-(2-Fluoro-4-hydroxymethyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

To dimethylamine (0.6 mL, 2.0 M, 1.0 mmol) in MeOH (5 mL) was added NaCNBH₃ (31 mg, 0.49 mmol). The mixture was heated to 50° C. for 1 hr, and then 4-(2-fluoro-4-formyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (39a) (100 mg, 0.24 mmol) was added. The reaction mixture was heated to 50° C. for 1 hr. Additional NaCNBH₃ (31 mg, 0.49 mmol) and dimethylamine (0.3 mL, 2.0 M, 0.5 mmol) were added to the reaction mixture. The mixture was heated at 50° C. for 1 hr, then concentrated and purified by reverse phase chromatograph to give 4-(4-dimethylaminomethyl-2-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (26 mg, 24% yield) and 4-(2-Fluoro-4-hydroxymethyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (25 mg, 25% yield) as white solid.

Example 39: ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1 H) 7.54-7.61 (m, 2 H) 7.28-7.37 (m, 2 H) 7.21 (d, J=1.01 Hz, 1 H) 6.97 (s, 1 H) 6.50 (d, J=2.27 Hz, 1 H) 4.27 (s, 2 H) 3.75 (s, 3 H) 2.97 (s, 2H) 2.74 (s, 6H) 1.46 (s, 6 H); LCMS for C₂₄H₂₇FN₄O₃ m/z 439.20 (M+H)⁺.

Example 40: ¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s, 1 H) 7.57 (d, J=2.27 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.16-7.22 (m, 2 H) 7.15 (d, J=1.01 Hz, 1 H) 6.86 (s, 1 H) 6.50 (d, J=2.27 Hz, 1 H) 5.36 (t, J=5.81 Hz, 1 H) 4.52 (d, J=5.81 Hz, 2 H) 3.75 (s, 3 H) 2.99 (s, 2 H) 1.45 (s, 6 H); LCMS for C₂₂H₂₂FN₃O₄ m/z 412.00 (M+H)⁺; Anal. Calcd. for C₂₂H₂₂FN₃O₄.0.08 TFA: C, 63.29; H, 5.29; N, 9.99; Found: C, 63.27; H, 5.29; N, 9.91.

Preparation of Intermediate 39a 4-(2-Fluoro-4-formyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 1f, from 3,4-difluoro-benzaldehyde and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a). ¹H NMR (400 MHz, CDCl₃) δ 9.92 (d, J=2.02 Hz, 1 H) 8.52 (s, 1 H) 7.72 (dd, J=10.36, 1.77 Hz, 1 H) 7.64 (d, J=8.34 Hz, 1 H) 7.28 (s, 1 H) 7.09 (t, J=7.96 Hz, 1 H) 7.05 (s, 1 H) 6.97 (s, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 3.78 (s, 3 H) 2.98 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₂H₂₀FN₃O₄ m/z 410.00 (M+H)⁺.

Examples 41-46 were prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) and the appropriate fluorophenyl amides. The appropriate fluorophenyl amide intermediates were prepared in a similar manner as described for Intermediate 32a, 33a or 35a, from the appropriate carboxylic acids or acid chlorides and amines.

Example 41 4-[2-Fluoro-4-(morpholine-4-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 42 4-[2-Fluoro-4-(4-methyl-piperazine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 43 4-[4-(3,3-Difluoro-azetidine-1-carbonyl)-2-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 44 4-[4-(3-Dimethylamino-azetidine-1-carbonyl)-2-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 45 4-[2-Fluoro-4-(3-hydroxy-azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 46 4-(4-Dimethylcarbamoyl-2-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example MW MF NMR m/z Elemental Analysis 41 494.5 C26H27FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1 H) 495.00 (M + H)⁺ Calcd. for C₂₆H₂₇FN₄O₅•0.29 7.27-7.31 (m, 2 H) 7.18 (d, J = 8.34 Hz, 1 AcOH•0.23 H₂O: C, H) 7.06 (t, J = 8.21 Hz, 1 H) 7.03 (s, 1 H) 61.86; H, 5.59; N, 10.86; 6.96 (s, 1 H) 6.77 (d, J = 2.02 Hz, 1 H) Found: C, 61.84; H, 5.41; N, 3.80 (s, 3 H) 3.67-3.78 (m, 8 H) 3.02 (s, 2 H) 10.99. 1.52 (s, 6 H); 42 507.6 C27H30FN5O4 ¹H NMR (400 MHz, CDCl₃) δ 9.49 (s, 1 H) 508.20 (M + H)⁺ Calcd. for C₂₇H₃₀FN₅O₄•1.82 7.30-7.34 (m, 2 H) 7.17-7.21 (m, 1 H) TFA: C, 51.44; H, 4.49; 7.11 (d, J = 8.08 Hz, 1 H) 7.08 (s, 1 H) N, 9.81; Found: C, 51.46; H, 6.96 (d, J = 1.26 Hz, 1 H) 6.86 (d, J = 2.27 Hz, 1 4.49; N, 9.79. H) 3.84 (s, 3 H) 3.55-3.63 (m, 4 H) 3.04 (s, 2 H) 2.86 (s, 3 H) 2.77-2.88 (m, 4 H) 1.53 (s, 6 H); 43 500.5 C25H23F3N4O4 ¹H NMR (400 MHz, CDCl₃) δ 10.16 (s, 1 501.00 (M + H)⁺ H) 7.50-7.55 (m, 1 H) 7.36-7.40 (m, 1 H) 7.35 (d, J = 2.53 Hz, 1 H) 7.17 (d, J = 1.26 Hz, 1 H) 7.11 (t, J = 8.08 Hz, 1 H) 7.04 (d, J = 1.26 Hz, 1 H) 6.95 (d, J = 2.53 Hz, 1 H) 4.58 (t, J = 11.87 Hz, 4 H) 3.88 (s, 3 H) 3.01 (s, 2 H) 1.48-1.55 (m, 6 H); 44 507.6 C27H30FN5O4 ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1 H) 508.20 (M + H)⁺ Calcd. for C₂₇H₃₀FN₅O₄•0.40 7.51 (d, J = 11.12 Hz, 1 H) 7.39 (d, J = 8.34 Hz, AcOH: C, 62.81; H, 1 H) 6.98-7.05 (m, 2 H) 6.94 (s, 1 H) 5.99; N, 13.17; Found: C, 6.76 (s, 1 H) 4.27-4.36 (m, 1 H) 62.94; H, 5.89; N, 13.17. 4.15-4.27 (m, 2 H) 3.99-4.11 (m, 1 H) 3.80 (s, 3 H) 3.10-3.19 (m, 1 H) 2.98 (s, 2 H) 2.20 (s, 6 H) 1.51 (s, 6 H); 45 480.5 C25H25FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 6 H) 481.00 (M + H)⁺ Calcd. for C₂₅H₂₅FN₄O₅•0.48 3.01 (s, 2 H) 3.71 (s, 3 H) 3.93-4.03 (m, TFA: C, 58.26; H, 4.80; 1 H) 4.19-4.30 (m, 1 H) 4.42-4.54 (m, 2 N, 10.47; Found: C, 58.30; H) 4.67-4.74 (m, 1 H) 6.78 (d, J = 2.27 Hz, H, 4.93; N, 10.28. 1 H) 6.82 (d, J = 1.01 Hz, 1 H) 7.01-7.07 (m, 2 H) 7.41 (d, J = 8.59 Hz, 1 H) 7.46 (dd, J = 10.99, 1.89 Hz, 1 H) 8.80 (s, 1 H); 46 452.5 C24H25FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1 H) 453.00 (M + H)⁺ Calcd. for C₂₄H₂₅FN₄O₄•0.25 7.30 (dd, J = 10.74, 1.89 Hz, 1 H) 7.28 (s, 1 H₂O•0.5 AcOH: C, H) 7.19 (d, J = 8.34 Hz, 1 H) 7.00-7.05 (m, 61.66; H, 5.69; N, 11.50; 2 H) 6.96 (s, 1 H) 6.77 (d, J = 2.27 Hz, 1 H) Found: C, 61.65; H, 5.41; N, 3.80 (s, 3 H) 3.10 (s, 3 H) 3.06 (s, 3 H) 11.51. 3.00 (s, 2 H) 1.51 (s, 6 H);

Examples 47-50 were prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) and the appropriate fluorophenyl amides. The appropriate fluorophenyl amide intermediates were prepared in a similar manner as described for Intermediate 32a, 33a or 35a, from the appropriate carboxylic acids or acid chlorides and amines.

Example 47 2,2-Dimethyl-4-[4-(morpholine-4-carbonyl)-phenoxy]-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 48 2,2-Dimethyl-4-[4-(pyrrolidine-1-carbonyl)-phenoxy]-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 49 4-[4-(3-Dimethylamino-azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 50 4-[4-(3,3-Difluoro-azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example MW MF NMR m/z Elemental Analysis 47 476.5 C26H28N4O5 ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1 H) 477.20 (M + H)⁺ Calcd. for C₂₆H₂₈N₄O₅•0.61 7.43 (s, 1 H) 7.41 (s, 1 H) 7.28 (s, 1 H) AcOH: C, 63.71; H, 5.98; N, 6.96-7.07 (m, 4 H) 6.79 (d, J = 2.27 Hz, 1 10.92; Found: C, 63.70; H, H) 3.81 (s, 3 H) 3.65-3.76 (m, 8 H) 5.73; N, 11.00. 2.93 (s, 2 H) 1.50 (s, 6 H); 48 460.5 C26H28N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1 H) 461.20 (M + H)⁺ Calcd. for C₂₆H₂₈N₄O₄•0.50 7.51-7.56 (m, 2 H) 7.29 (d, J = 2.27 Hz, 1 AcOH: C, 62.66; H, 5.53; N, H) 7.05 (dd, J = 9.73, 1.39 Hz, 2 H) 10.84; Found: C, 62.66; H, 6.97-7.01 (m, 2 H) 6.82 (d, J = 2.53 Hz, 1 H) 5.55; N, 10.83. 3.82 (s, 3 H) 3.66 (t, J = 6.82 Hz, 2 H) 3.50 (t, J = 6.44 Hz, 2 H) 2.91 (s, 2 H) 1.88-2.00 (m, 4 H) 1.49 (s, 6 H); 49 489.6 C27H31N5O4 ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1 H) 490.20 (M + H)⁺ 7.60-7.66 (m, 2 H) 7.28 (s, 1 H) 7.02-7.07 (m, 2 H) 6.96-7.01 (m, 2 H) 6.78 (d, J = 2.27 Hz, 1 H) 4.22-4.34 (m, 3 H) 4.06-4.18 (m, 1 H) 3.80 (s, 3 H) 3.20-3.30 (m, 1 H) 2.90 (s, 2 H) 2.29 (s, 6 H) 1.49 (s, 6 H); 50 482.5 C25H24F2N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1 H) 483.00 (M + H)⁺ Calcd. for C₂₅H₂₄F₂N₄O₄•0.22 7.63-7.67 (m, 2 H) 7.28 (d, J = 2.27 Hz, 1 H2O•0.17 AcOH: C, H) 7.10 (d, J = 1.26 Hz, 1 H) 7.06 (d, 61.28; H, 5.10; N, 11.28; J = 1.26 Hz, 1 H) 7.00-7.04 (m, 2 H) Found: C, 61.28; H, 5.00; N, 6.81 (d, J = 2.27 Hz, 1 H) 4.56 (t, J = 12.00 11.38. Hz, 4 H) 3.80 (s, 3 H) 2.91 (s, 2 H) 1.50 (s, 6 H);

Examples 51-64 were prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) and the appropriate fluorophenyl amides. The appropriate fluorophenyl amide intermediates were prepared in a similar manner as described for Intermediate 32a, 33a or 35a, from the appropriate carboxylic acids or acid chlorides and amines.

Example 65 was prepared in a similar manner as described for Example 1, from 1-methyl-3-aminopyrazole and 4-(4-benzyloxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (65b).

Preparation of Intermediate 65a 4-Bromo-2-fluoro-benzoic acid benzyl ester

Benzyl bromide (2.80 mL, 23.6 mmol) was added to a solution of 2-fluro-4-bromobenzoic acid (4.34 g, 19.8 mmol) and Cs₂CO₃ (9.79 g, 30.0 mmol) in CH₂Cl₂ (50 mL). The mixture was heated to reflux for 4 hr. The reaction was quenched with H₂O (150 mL) and extracted with CH₂Cl₂ (150 mL). The organic layer was dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 10% EtOAc in hexanes to give a colorless oil (6.27 g, 100% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.88 (m, 1 H) 7.44-7.47 (m, 2 H) 7.34-7.42 (m, 5 H) 5.38 (s, 2 H).

Preparation of Intermediate 65b 4-(4-Benzyloxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-benzoic acid benzyl ester (65a) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (t, J=8.46 Hz, 1 H) 7.44-7.49 (m, 2 H) 7.32-7.43 (m, 3 H) 7.28 (s, 1 H) 7.25 (s, 1 H) 6.76 (dd, J=8.72, 2.40 Hz, 1 H) 6.68 (dd, J=11.75, 2.40 Hz, 1 H) 5.38 (s, 2H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C₂₆H₂₃FO₆ m/z 450.00 (M+H)⁺.

Examples 66-76 were prepared in a similar manner as described for Example 15, from 4-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-2-fluoro-benzoic acid (66d) and the appropriate amines.

Preparation of Intermediate 66a 4-(4-tert-Butoxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-benzoic acid tert-butyl ester and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e). ¹H NMR (400 MHz, CDCl₃) δ 7.86 (t, J=8.59 Hz, 1 H) 7.25-7.31 (m, 1 H) 7.24 (s, 1 H) 6.74 (dd, J=8.84, 2.02 Hz, 1H) 6.65 (dd, J=11.87, 2.27 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.59 (s, 9 H) 1.48 (s, 6 H); LCMS for C₂₃H₂₅FO₆ m/z 439.00 (M+Na)⁺.

Preparation of Intermediate 66b 4-(4-tert-Butoxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid

NaOH (6.20 mL, 19.0 mmol, 3N aqueous solution) was added to a solution of 4-(4-tert-butoxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (66a) (2.56 g, 5.91 mmol) in 30 mL MeOH. The reaction mixture was heated to 60° C. for 2 hr, concentrated, diluted with H₂O (100 mL), acidified with 1N aqueous HCl to Ph ˜1, and extracted with CH₂Cl₂ (2×100 mL). The combined organic layer was dried over MgSO₄, concentrated in vacuo to give a white solid (2.46 g, 98% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (br. s., 1 H) 7.85 (t, J=8.72 Hz, 1 H) 7.11 (d, J=1.26 Hz, 1 H) 7.06 (d, J=1.01 Hz, 1 H) 6.99 (dd, J=12.13, 2.27 Hz, 1 H) 6.89 (dd, J=8.72, 2.40 Hz, 1 H) 2.87 (s, 2 H) 1.53 (s, 9H) 1.42 (s, 6 H); LCMS for C₂₂H₂₃FO₆m/z 425.00 (M+Na)⁺.

Preparation of Intermediate 66c 4-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-2-fluoro-benzoic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Example 15 except that the reaction was carried out at 75° C. for 2 hr, from 1-methyl-3-aminopyrazole (892 mg, 9.18 mmol) and 4-(4-tert-butoxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (66b) (2.46 g, 6.11 mmol) to give a white solid (1.77 g, 60% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H) 7.87 (t, J=8.59 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.07 (s, 1 H) 7.04 (s, 1 H) 6.79 (d, J=2.02 Hz, 1 H) 6.75 (dd, J=8.84, 2.27 Hz, 1 H) 6.68 (dd, J=11.75, 2.40 Hz, 1H) 3.80 (s, 3 H) 2.87 (s, 2 H) 1.60 (s, 9 H) 1.49 (s, 6H); LCMS for C₂₆H₂₈FN₃O₅ m/z 505.00 (M+Na)⁺.

Preparation of Intermediate 66d 4-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-2-fluoro-benzoic acid

To a solution of 4-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-2-fluoro-benzoic acid tert-butyl ester (66c) (1.77 g, 3.68 mmol) in CH₂Cl₂ (10 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 2 hr, concentrated, and dried under vacuum to give an off-white solid (TFA salt) (2.0 g, 100% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1 H) 7.91 (t, J=8.72 Hz, 1 H) 7.59 (d, J=2.02 Hz, 1 H) 7.25 (s, 2 H) 6.98 (dd, J=12.13, 2.02 Hz, 1 H) 6.89 (dd, J=8.72, 2.15 Hz, 1 H) 6.55 (d, J=1.77 Hz, 1 H) 3.76 (s, 3 H) 2.87 (s, 2 H) 1.43 (s, 6 H); LCMS for C₂₂H₂₀FN₃O₅ m/z 425.00 (M+H)⁺.

Example 51 4-[3-Fluoro-4-(morpholine-4-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 52 4-[4-(3,3-Difluoro-azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 53 4-[3-Fluoro-4-(4-methyl-piperazine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 54 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 55 4-[3-Fluoro-4-(3-hydroxy-azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 56 4-[3-Fluoro-4-(pyrrolidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 57 4-[4-(3-Dimethylamino-azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 58 4-[3-Fluoro-4-((R)-3-fluoro-pyrrolidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 59 4-[3-Fluoro-4-((R)-3-methoxy-pyrrolidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 60 4-[3-Fluoro-4-((S)-3-methoxy-pyrrolidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 61 4-[3-Fluoro-4-(piperidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 62 4-[3-Fluoro-4-((S)-3-hydroxy-pyrrolidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 63 4-[3-Fluoro-4-((S)-3-fluoro-pyrrolidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 64 4-{3-Fluoro-4-[(2-methoxy-ethyl)-methyl-carbamoyl]-phenoxy}-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 65 4-[3-Fluoro-4-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 66 4-{3-Fluoro-4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-phenoxy}-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 67 4-[4-(Cyanomethyl-methyl-carbamoyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 68 4-[3-Fluoro-4-(2-methoxy-ethylcarbamoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 69 4-(3-Fluoro-4-methylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 70 4-(4-Ethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 71 4-(3-Fluoro-4-isopropylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 72 4-[3-Fluoro-4-(2-hydroxy-ethylcarbamoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 73 4-(4-Cyclopropylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 74 4-(4-Cyclobutylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 75 4-[3-Fluoro-4-(2-fluoro-ethylcarbamoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example 76 4-[4-(2,2-Difluoro-ethylcarbamoyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

Example MW MF NMR m/z Elemental Analysis 51 494.5 C26H27FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 10.16 (s, 1 495.00 (M + H)⁺ Calcd. for C₂₆H₂₇FN₄O₅•0.43 H) 7.50-7.55 (m, 1 H) 7.36-7.40 (m, 1 AcOH: C, 62.00; H, H) 7.35 (d, J = 2.53 Hz, 1 H) 7.17 (d, 5.56; N, 10.77; Found: C, J = 1.26 Hz, 1 H) 7.11 (t, J = 8.08 Hz, 1 H) 61.99; H, 5.46; N, 10.99. 7.04 (d, J = 1.26 Hz, 1 H) 6.95 (d, J = 2.53 Hz, 1 H) 4.58 (t, J = 11.87 Hz, 4 H) 3.88 (s, 3 H) 3.01 (s, 2 H) 1.48-1.55 (m, 6 H); 52 500.5 C25H23F3N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H) 501.00 (M + H)⁺ Calcd. for C₂₅H₂₃F₃N₄O₄•0.75 7.64 (t, J = 8.21 Hz, 1 H) 7.29 (d, J = 2.27 Hz, H₂O: C, 58.42; H, 4.80; 1 H) 7.08 (dd, J = 9.47, 1.39 Hz, 2 H) N, 10.90; Found: C, 58.62; 6.84 (dd, J = 8.72, 2.40 Hz, 1 H) 6.79 (d, H, 4.59; N, 10.62. J = 2.27 Hz, 1 H) 6.70 (dd, J = 11.62, 2.27 Hz, 1 H) 4.44-4.55 (m, 4 H) 3.82 (s, 3 H) 2.91 (s, 2 H) 1.50 (s, 6 H); 53 507.6 C27H30FN5O4 ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1 H) 508.20 (M + H)⁺ Calcd. for C₂₇H₃₀FN₅O₄•0.42 7.34-7.40 (m, 1 H) 7.29 (d, J = 2.27 Hz, 1 AcOH: C, 62.76; H, H) 7.05-7.09 (m, 2 H) 6.77-6.82 (m, 2 5.99; N, 13.14; Found: C, H) 6.70 (dd, J = 10.61, 2.27 Hz, 1 H) 62.76; H, 5.82; N, 13.22. 3.82-3.85 (m, 2 H) 3.81 (s, 3 H) 3.36-3.46 (m, 2 H) 2.91 (s, 2 H) 2.47-2.57 (m, 2 H) 2.37-2.46 (m, 2 H) 2.34 (s, 3 H) 1.50 (s, 6 H); 54 452.5 C24H25FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1 H) 453.00 (M + H)⁺ Calcd. for C₂₄H₂₅FN₄O₄•0.34 7.33-7.41 (m, 1 H) 7.28 (d, J = 2.02 Hz, 1 AcOH: C, 62.68; H, H) 7.05-7.09 (m, 2 H) 6.77-6.82 (m, 2 5.62; N, 11.85; Found: C, H) 6.69 (dd, J = 10.61, 2.27 Hz, 1 H) 62.66; H, 5.60; N, 11.97. 3.81 (s, 3 H) 3.13 (s, 3 H) 2.99 (d, J = 1.77 Hz, 3 H) 2.90 (s, 2 H) 1.50 (s, 6 H); 55 480.5 C25H25FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 481.00 (M + H)⁺ Calcd. for C₂₅H₂₅FN₄O₅•0.34 7.91-7.99 (m, 2 H) 7.34 (t, J = 6.69 Hz, 2 H) AcOH: C, 62.68; H, 7.09-7.17 (m, 2 H) 5.05 (d, J = 2.78 Hz, 1 H) 5.62; N, 11.85; Found: C, 3.88-3.97 (m, 1 H) 3.73-3.82 (m, 1 H) 62.66; H, 5.60; N, 11.97. 3.15-3.24 (m, 1 H) 3.09-3.15 (m, 4 H) 2.99 (dd, J = 16.55, 7.20 Hz, 1 H) 1.62 (s, 9 H); 56 478.5 C26H27FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1 H) 479.00 (M + H)⁺ 7.40 (t, J = 8.08 Hz, 1 H) 7.29 (d, J = 2.02 Hz, 1 H) 7.09 (d, J = 3.03 Hz, 2 H) 6.77-6.83 (m, 2 H) 6.70 (dd, J = 10.74, 2.15 Hz, 1 H) 3.82 (s, 3 H) 3.65 (t, J = 6.95 Hz, 2 H) 3.38 (t, J = 6.57 Hz, 2 H) 2.90 (s, 2 H) 1.89-2.00 (m, 4 H) 1.50 (s, 6 H); 57 507.6 C27H30FN5O4 ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1 H) 508.20 (M + H)⁺ Calcd. for C₂₇H₃₀FN₅O₄•0.60 7.54 (t, J = 8.21 Hz, 1 H) 7.28 (d, J = 2.27 Hz, H2O: C, 61.95; H, 1 H) 7.08 (d, J = 2.53 Hz, 2 H) 6.79 (d, 6.08; N, 13.14; Found: C, J = 1.77 Hz, 1 H) 6.67 (dd, J = 11.12, 2.27 Hz, 61.87; H, 5.87; N, 13.16. 1 H) 4.23 (dd, J = 10.11, 7.58 Hz, 1 H) 4.09-4.17 (m, 1 H) 4.01-4.09 (m, 2 H) 3.81 (s, 3 H) 3.15-3.25 (m, 1 H) 2.89 (s, 2 H) 2.24 (s, 6 H) 2.06 (s, 1 H) 1.49 (s, 6 H); 58 496.5 C26H26F2N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1 H) 496.00 (M + H)⁺ Calcd. for C₂₆H₂₆F₂N₄O₄•0.82 7.40-7.47 (m, 1 H) 7.29 (d, J = 2.27 Hz, 1 H2O: C, 61.08; H, H) 7.06-7.08 (m, 2 H) 6.77-6.83 (m, 2 5.45; N, 10.96; Found: C, H) 6.65-6.74 (m, 1 H) 4.86-5.64 (m, 1 61.07; H, 5.17; N, 10.79. H) 3.87-3.96 (m, 1 H) 3.82 (s, 3 H) 3.60-3.71 (m, 2 H) 3.54 (t, J = 9.47 Hz, 1 H) 2.91 (d, J = 1.77 Hz, 2 H) 2.29 (d, J = 4.55 Hz, 1 H) 2.01-2.13 (m, 1 H) 1.50 (s, 6 H); 59 508.6 C27H29FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 8.85 (d, 509.00 (M + H)⁺ Calcd. for C₂₇H₂₉FN₄O₅•0.44 J = 4.04 Hz, 1 H) 7.39-7.44 (m, 1 H) AcOH: C, 62.60; H, 7.28 (d, J = 2.27 Hz, 1 H) 7.08-7.12 (m, 2 H) 5.80; N, 10.47; Found: C, 6.81 (d, J = 2.27 Hz, 1 H) 6.79 (t, J = 2.15 Hz, 62.60; H, 5.69; N, 10.45. 1 H) 6.68-6.73 (m, 1 H) 4.02-4.11 (m, 0.5 H) 3.94-4.00 (m, 0.5 H) 3.81 (s, 3 H) 3.68-3.78 (m, 2 H) 3.49-3.62 (m, 1 H) 3.38-3.46 (m, 1 H) 3.37 (s, 1.5 H) 3.28-3.32 (m, 1.5 H) 2.90 (s, 2 H) 1.92-2.16 (m, 2 H) 1.50 (s, 6 H); 60 508.6 C27H29FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1 H) 509.00 (M + H)⁺ Calcd. for C₂₇H₂₉FN₄O₅•0.25 7.38-7.45 (m, 1 H) 7.28 (d, J = 2.27 Hz, 1 H₂O•0.37 AcOH: C, H) 7.04-7.09 (m, 2 H) 6.76-6.83 (m, 2 62.25; H, 5.83; N, 10.47; H) 6.62-6.72 (m, 1 H) 4.02-4.09 (m, 0.5 Found: C, 62.24; H, 5.47; N, H) 3.92-4.01 (m, 05 H) 3.80 (s, 3 H) 10.69. 3.71-3.78 (m, 2 H) 3.49-3.58 (m, 1 H) 3.39-3.46 (m, 1 H) 3.37 (s, 1.5 H) 3.27-3.32 (m, 1.5 H) 2.89 (s, 2 H) 1.90-2.19 (m, 2 H) 1.49 (s, 6 H); 61 492.6 C27H29FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1 H) 493.00 (M + H)⁺ Calcd. for C₂₇H₂₉FN₄O₄•0.40 7.30-7.37 (m, 1 H) 7.28 (d, J = 2.27 Hz, 1 H2O: C, 64.89; H, H) 7.05-7.08 (m, 2 H) 6.76-6.82 (m, 2 6.01; N, 11.21; Found: C, H) 6.69 (dd, J = 10.61, 2.27 Hz, 1 H) 64.88; H, 5.89; N, 10.98. 3.81 (s, 3 H) 3.69-3.78 (m, 2 H) 3.27-3.37 (m, 2 H) 2.91 (s, 2 H) 1.62-1.73 (m, 4 H) 1.52-1.62 (m, 2 H) 1.50 (s, 6 H); 62 494.5 C26H27FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1 H) 495.00 (M + H)⁺ 7.38-7.45 (m, 1 H) 7.28 (d, J = 2.27 Hz, 1 H) 7.04-7.09 (m, 2 H) 6.76-6.83 (m, 2 H) 6.62-6.72 (m, 1 H) 4.02-4.09 (m, 0.5 H) 3.92-4.01 (m, 05 H) 3.80 (s, 3 H) 3.71-3.78 (m, 2 H) 3.49-3.58 (m, 1 H) 3.39-3.46 (m, 1 H) 3.37 (s, 1.5 H) 3.27-3.32 (m, 1.5 H) 2.89 (s, 2 H) 1.90-2.19 (m, 2 H) 1.49 (s, 6 H); 63 496.5 C26H26F2N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1 H) 497.20 (M + H)⁺ Calcd. for C₂₆H₂₆F₂N₄O₄•0.65 7.40-7.48 (m, 1 H) 7.28 (d, J = 2.27 Hz, 1 H₂O•0.60 AcOH: C, H) 7.05-7.11 (m, 2 H) 6.82 (t, J = 2.15 Hz, 60.03; H, 5.50; N, 10.29; 1 H) 6.80 (d, J = 2.02 Hz, 1 H) 6.71 (ddd, Found: C, 59.86; H, 5.16; N, J = 10.61, 7.83, 2.27 Hz, 1 H) 10.33. 4.83-5.83 (m, 1 H) 3.86-3.96 (m, 2 H) 3.81 (s, 3 H) 3.59-3.71 (m, 2 H) 2.91 (s, 2 H) 2.29-2.41 (m, 1 H) 2.01-2.12 (m, 1 H) 1.50 (s, 6 H); 64 496.5 C26H29FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1 H) 497.00 (M + H)⁺ Calcd. for C₂₆H₂₉FN₄O₅•0.30 7.31-7.39 (m, 1 H) 7.28 (d, J = 2.27 Hz, 1 AcOH: C, 62.09; H, H) 7.07 (s, 2 H) 6.76-6.81 (m, 2 H) 5.92; N, 10.89; Found: C, 6.69 (dt, J = 10.42, 2.75 Hz, 1 H) 3.80 (s, 3 H) 61.95; H, 5.90; N, 10.99. 3.73 (t, J = 4.93 Hz, 1 H) 3.67 (t, J = 4.80 Hz, 1 H) 3.42-3.47 (m, 1 H) 3.40 (s, 2 H) 3.28 (s, 1 H) 3.15 (s, 1 H) 3.01-3.07 (m, 2 H) 2.90 (s, 2 H) 1.49 (s, 6 H); 65 504.5 C26H25FN6O4 ¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, 505.00 (M + H)⁺ Calcd. for C₂₆H₂₅FN₆O₄•0.35 J = 14.15 Hz, 1 H) 8.53 (s, 1 H) 8.15 (t, H₂O•0.10EtOAc: C, J = 8.84 Hz, 1 H) 7.29 (d, J = 2.27 Hz, 1 H) 61.02; H, 5.17; N, 16.14; 7.28 (s, 1 H) 7.09 (s, 2 H) 6.87 (dd, Found: C, 61.02; H, 5.14; N, J = 8.59, 2.27 Hz, 1 H) 6.81 (d, J = 2.27 Hz, 16.17. 1 H) 6.78 (d, J = 2.02 Hz, 1 H) 6.73 (dd, J = 13.14, 2.27 Hz, 1 H) 3.83 (s, 3 H) 3.78 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); 66 482.5 C25H27FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 483.00 (M + H)⁺ Calcd. for C₂₅H₂₇FN₄O₅•0.69 8.93-9.59 (m, 1 H) 7.31-7.46 (m, 1 H) 7.28 (d, H₂O: C, 60.67; H, 5.78; J = 2.02 Hz, 1 H) 7.09-7.18 (m, 2 H) N, 11.32; Found: C, 60.68; 6.76-6.88 (m, 2 H) 6.71 (dd, J = 10.61, 2.27 Hz, H, 5.52; N, 11.09. 1 H) 3.92 (t, J = 5.18 Hz, 2 H) 3.80 (s, 3 H) 3.67-3.77 (m, 2 H) 3.43 (t, J = 5.56 Hz, 1 H) 3.16 (s, 1 H) 3.04 (d, J = 1.77 Hz, 2 H) 2.90 (s, 2 H) 1.50 (s, 6 H); 67 477.5 C25H24FN5O4 ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1 H) 478.00 (M + H)⁺ Calcd. for C₂₅H₂₄FN₅O₄•0.45 7.43 (t, J = 8.21 Hz, 1 H) 7.29 (d, J = 2.02 Hz, AcOH: C, 61.66; H, 1 H) 7.13 (s, 1 H) 7.12 (s, 1 H) 5.15; N, 13.88; Found: C, 6.85 (dd, J = 8.46, 1.64 Hz, 1 H) 6.81 (d, J = 2.27 Hz, 61.65; H, 5.05; N, 13.95. 1 H) 6.73 (d, J = 10.86 Hz, 1 H) 4.52 (s, 2 H) 3.81 (s, 3 H) 3.13 (s, 3 H) 2.91 (s, 2 H) 1.50 (s, 6 H); 68 482.5 C25H27FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1 H) 483.00 (M + H)⁺ Calcd. for C₂₅H₂₇FN₄O₅•0.69 8.09 (t, J = 8.84 Hz, 1 H) 7.28 (d, J = 2.27 Hz, H₂O: C, 60.66; H, 5.53; 1 H) 7.12 (s, 1 H) 7.09 (s, 1 H) N, 11.10; Found: C, 60.67; 6.97-7.07 (m, 1 H) 6.85 (dd, J = 8.59, 2.27 Hz, 1 H, 5.78; N, 11.32. H) 6.80 (d, J = 2.02 Hz, 1 H) 6.71 (dd, J = 13.14, 2.27 Hz, 1 H) 3.81 (s, 3 H) 3.68 (q, J = 5.05 Hz, 2 H) 3.58 (t, J = 5.05 Hz, 2 H) 3.41 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); 69 438.5 C23H23FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1 H) 439.00 (M + H)⁺ Calcd. for C₂₃H₂₃FN₄O₄•0.50 8.10 (t, J = 8.97 Hz, 1 H) 7.29 (d, J = 2.27 Hz, H₂O•0.78 AcOH: C, 1 H) 7.16 (d, J = 1.26 Hz, 1 H) 7.13 (d, 59.68; H, 5.53; N, 11.33; J = 1.26 Hz, 1 H) 6.86 (dd, J = 8.72, 2.40 Hz, Found: C, 59.66; H, 5.34; N, 1 H) 6.82 (d, J = 2.27 Hz, 1 H) 6.70 (dd, 11.50. J = 13.14, 2.27 Hz, 1 H) 3.81 (s, 3 H) 3.04 (d, J = 4.04 Hz, 2 H) 2.89 (s, 2 H) 2.07 (s, 2 H) 1.49 (s, 6 H); 70 452.5 C24H25FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1 H) 453.00 (M + H)⁺ Calcd. for C₂₄H₂₅FN₄O₄•0.43 8.09 (t, J = 8.97 Hz, 1 H) 7.28 (d, J = 2.27 Hz, AcOH: C, 62.42; H, 1 H) 7.11 (d, J = 1.01 Hz, 1 H) 7.08 (d, 5.63; N, 11.71; Found: C, J = 1.26 Hz, 1 H) 6.85 (dd, J = 8.84, 2.27 Hz, 62.42; H, 5.59; N, 11.87. 1 H) 6.80 (d, J = 2.27 Hz, 1 H) 6.70 (dd, J = 13.14, 2.53 Hz, 1 H) 6.65 (br. s., 1 H) 3.80 (s, 3 H) 3.48-3.56 (m, 2 H) 2.88 (s, 2 H) 1.49 (s, 6 H) 1.27 (t, J = 7.33 Hz, 3 H); 71 466.5 C25H27FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1 H) 467.00 (M + H)⁺ Calcd. for C₂₅H₂₇FN₄O₄•0.75 8.08 (t, J = 8.97 Hz, 1 H) 7.28 (d, J = 2.27 Hz, AcOH: C, 62.22; H, 1 H) 7.13-7.16 (m, 1 H) 7.11 (d, 5.91; N, 10.95; Found: C, J = 1.26 Hz, 1 H) 6.86 (dd, J = 8.72, 2.40 Hz, 62.17; H, 5.74; N, 11.06. 1 H) 6.82 (d, J = 2.27 Hz, 1 H) 6.70 (dd, J = 13.26, 2.40 Hz, 1 H) 6.48 (dd, J = 12.51, 7.71 Hz, 1 H) 4.26-4.36 (m, 1 H) 3.80 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H) 1.28 (d, J = 6.57 Hz, 6 H); 72 468.5 C24H25FN4O5 ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 1 H) 469.00 (M + H)⁺ Calcd. for C₂₄H₂₅FN₄O₅•0.60 8.05 (t, J = 8.84 Hz, 1 H) 7.26 (d, J = 2.27 Hz, AcOH: C, 59.99; H, 1 H) 7.18 (br. s., 1 H) 7.15 (s, 1 H) 5.47; N, 11.10; Found: C, 7.10 (s, 1 H) 6.85 (dd, J = 8.72, 2.40 Hz, 1 59.83; H, 5.47; N, 11.27. H) 6.78 (d, J = 2.02 Hz, 1 H) 6.69 (dd, J = 13.14, 2.27 Hz, 1 H) 3.82-3.87 (m, 2 H) 3.76 (s, 3 H) 3.66 (q, J = 4.80 Hz, 2 H) 2.89 (s, 2 H) 1.49 (s, 6 H); 73 464.5 C25H25FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 465.00 (M + H)⁺ Calcd. for C₂₅H₂₅FN₄O₄•0.75 8.03-8.13 (m, 1 H) 7.49 (s, 1 H) 7.20 (s, 1 H) H₂O•0.33 EtOAc: C, 7.06-7.14 (m, 2 H) 6.77-6.87 (m, 2 H) 62.34; H, 5.79; N, 11.05; 6.65-6.74 (m, 1 H) 4.03 (s, 3 H) 2.91-2.97 (m, Found: C, 62.35; H, 5.59; N, 1 H) 2.88 (s, 2 H) 1.48 (s, 6 H) 10.98. 0.83-0.91 (m, 2 H) 0.59-0.68 (m, 2 H); 74 478.5 C26H27FN4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, 479.00 (M + H)⁺ Calcd. for C₂₆H₂₇FN₄O₄•0.69 J = 9.60 Hz, 1 H) 7.51 (s, 1 H) 7.21 (s, 1 H) H₂O: C, 63.61; H, 5.83; 7.10 (s, 2 H) 6.84 (d, J = 7.83 Hz, 2 H) N, 11.41; Found: C, 63.66; 6.66-6.78 (m, 1 H) 4.54-4.65 (m, 1 H) H, 5.58; N, 10.06. 4.05 (s, 3 H) 2.88 (s, 2 H) 2.39-2.49 (m, 2 H) 1.93-2.05 (m, 2 H) 1.73-1.83 (m, 2 H) 1.48 (s, 6 H); 75 470.5 C24H24F2N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1 H) 471.20 (M + H)⁺ Calcd. for C₂₄H₂₄F₂N₄O₄•0.73 8.07 (t, J = 8.97 Hz, 1 H) 7.27 (d, J = 2.27 Hz, H2O•0.40 EtOAc: C, 1 H) 7.10 (s, 1 H) 7.07 (s, 1 H) 59.26; H, 5.57; N, 10.80; 6.96-7.05 (m, 1 H) 6.83 (dd, J = 8.84, 2.27 Hz, 1 Found: C, 59.25; H, 5.54; N, H) 6.78 (d, J = 2.27 Hz, 1 H) 6.69 (dd, 10.73. J = 13.14, 2.53 Hz, 1 H) 4.66 (t, J = 4.80 Hz, 1 H) 4.54 (t, J = 4.80 Hz, 1 H) 3.80-3.87 (m, 1 H) 3.78 (s, 3 H) 3.72-3.77 (m, 1 H) 2.86 (s, 2 H) 1.47 (s, 6 H); 76 488.5 C24H23F3N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1 H) 489.00 (M + H)⁺ Calcd. for C₂₄H₂₃F₃N₄O₄•0.09 8.08 (t, J = 8.84 Hz, 1 H) 7.28 (s, 1 H) H₂O: C, 58.82; H, 4.77; 7.09 (s, 1 H) 7.06 (d, J = 1.26 Hz, 1 H) N, 11.43; Found: C, 58.88; 6.90-7.01 (m, 1 H) 6.86 (dd, J = 8.72, 2.40 Hz, 1 H, 4.75; N, 11.33. H) 6.78 (d, J = 2.27 Hz, 1 H) 6.71 (dd, J = 13.26, 2.40 Hz, 1 H) 5.66-6.26 (m, 1 H) 3.81-3.91 (m, 2 H) 3.79 (s, 3 H) 2.89 (s, 2 H) 1.49 (s, 6 H);

Example 77 6-[(4-Benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-nicotinic acid

NaOH (110 uL, 0.1 mmol, 3N aqueous solution) was added to a solution of 6-[(4-benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-nicotinic acid methyl ester (77c) (48 mg, 0.11 mol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and purified by reverse phase chromatograph to give a white solid (10 mg, 22% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, 1 H) 8.31-8.41 (m, 1 H) 8.21-8.31 (m, 1 H) 7.47-7.54 (m, 2 H) 7.42 (t, J=7.33 Hz, 1 H) 7.35 (t, J=7.07 Hz, 1 H) 7.23 (s, 1 H) 7.00 (s, 1 H) 5.24 (s, 2 H) 3.06 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₄H₂₂N₂O₅ m/z 419.00 (M+H)⁺.

Preparation of Intermediate 77a 4-Benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) was dissolved in DMF (50 mL). K₂CO₃ (6.48 g, 46.9 mmol) and benzyl bromide (2.80 mL, 23.6 mmol) were added. The reaction mixture was stirred at room temperature overnight, quenched with H₂O (150 mL), and extracted with EtOAc (2×150 mL). The organic layers were dried over MgSO₄ and concentrated to give a white solid (7.18g, 98% yield) which was used as it is for the next step. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.46 (m, 5 H) 7.21 (s, 1 H) 7.08 (s, 1 H) 5.13 (s, 2 H) 3.90 (s, 3 H) 3.02 (s, 2 H) 1.49 (s, 6 H); LCMS for C₁₉H₂₀O₄ m/z 313.20 (M+H)⁺.

Preparation of Intermediate 77b 4-Benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid

NaOH (23 mL, 69 mmol, 3N aqueous solution) was added to a solution of 4-benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (77a) (7.18 g, 23 mmol) in MeOH (80 mL). The reaction mixture was heated to 60° C. for 3 hr, and concentrated in vacuo. The residue was diluted with H₂O (100 mL) and washed with EtOAc (100 mL). The aqueous phase was acidified with 3N aqueous HCl to Ph ˜2 to form a white precipitate, which was filtered and dried to give a white solid (6.05 g, 88% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1 H) 7.38-7.48 (m, 4 H) 7.33 (t, J=7.07 Hz, 1 H) 7.14 (s, 1 H) 6.88 (s, 1H) 5.17 (s, 2 H) 2.98 (s, 2 H) 1.42 (s, 6 H); LCMS for C₁₈H₁₈O₅ m/z 299.10 (M+H)⁺.

Preparation of Intermediate 77c 6-[(4-Benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-nicotinic acid methyl ester

Thionyl chloride (40 uL, 0.55 mmol) and DMF (3 drops) were added to a solution of 4-benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (77b) (130 mg, 0.44 mmol) in CH₂Cl₂ (20 mL). The mixture was concentrated and dried to give an off-white solid (130 mg). The solid was dissolved in CH₂Cl₂ (10 mL) and added pyridine (40 uL, 0.49 mmol) and methyl 6-aminonicotinate (65 mg, 0.43 mmol). The reaction mixture was stirred at room temperature for 2 hr, then quenched with H₂O (15 mL), and extracted with EtOAc (2×15 mL). The organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 25% EtOAc in hexanes to give a white solid (44 mg, 25% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.51 (s, 6 H) 3.05 (s, 2 H) 3.95 (s, 3 H) 5.16 (s, 2 H) 6.90 (d, J=1.26 Hz, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 7.34-7.38 (m, 1 H) 7.39-7.47 (m, 4 H) 8.36 (dd, J=8.72, 2.15 Hz, 1 H) 8.40-8.47 (m, 1 H) 8.65 (s, 1 H) 8.94 (d, J=1.52 Hz, 1 H); LCMS for C₂₅H₂₄N₂O₅ m/z 433.00 (M+H)⁺.

Example 78 2,2-Dimethyl-4-((S)-1-methyl-2-phenyl-ethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 2,2-dimethyl-4-((S)-1-methyl-2-phenyl-ethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (78a). ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1 H) 7.26-7.32 (m, 3 H) 7.20-7.25 (m, 3 H) 6.95 (s, 1 H) 6.81 (d, J=2.02 Hz, 1 H) 6.76 (s, 1 H) 4.63-4.71 (m, 1 H) 3.79 (s, 3 H) 3.04 (dd, J=13.77, 6.44 Hz, 1 H) 2.85-2.93 (m, 3 H) 1.48 (d, J=3.79 Hz, 6 H) 1.33 (d, J=6.06 Hz, 3 H); LCMS for C₂₄H₂₇N₃O₃ m/z 406.20 (M+H)⁺; Anal. Calcd. for C₂₄H₂₇N₃O₃.0.24 H₂O: C, 70.34; H, 6.76; N, 10.25; Found: C, 70.40; H, 6.72; N, 10.26.

Preparation of Intermediate 78a 2,2-Dimethyl-4-((S)-1-methyl-2-phenyl-ethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

4-Hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxy-lic acid methyl ester (3e) (1.04 g, 4.69 mmol) was dissolved in CH₂Cl₂ (25 mL) and cooled to 0° C. whilst stirring under a N₂ atmosphere. The solution was treated with Ph₃P (1.85 g, 7.04 mmol), (R)-(−)-1-phenyl-2-propane (959 mg, 7.04 mmol) and DIAD (1.40 mL, 7.11 mmol) added drop wise. The resulting solution was stirred at RT for 2 h. The reaction mixture was filtered and washed with CH₂Cl₂, concentrated in vacuo and purified by flash column chromatography eluting with 20% EtOAc/hexane to afford a colorless oil (1.27 g, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.34 (d, J=6.06 Hz, 3 H) 1.47 (d, J=3.54 Hz, 6 H) 2.83-2.89 (m, 3 H) 3.02-3.09 (m, 1 H) 3.88 (s, 3 H) 4.62-4.71 (m, 1 H) 7.02 (s, 1 H) 7.12 (s, 1 H) 7.21-7.32 (m, 5 H); LCMS for C₂₁H₂₄O₄ m/z 341.20 (M+H)⁺.

Example 79 4-[2-(4-Methoxy-phenyl)-1-methyl-ethoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 78a, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a). ¹H NMR (400 MHz, CDCl₃) δ 9.32 (s, 1 H) 7.33 (s, 1 H) 7.15 (d, J=8.59 Hz, 2 H) 7.02 (s, 1 H) 6.92 (s, 1 H) 6.87 (s, 1 H) 6.83 (d, J=8.84 Hz, 2 H) 4.68-4.77 (m, 1 H) 3.86 (s, 3 H) 3.78 (s, 3 H) 2.90-2.99 (m, 3 H) 2.82-2.88 (m, 1 H) 1.49 (s, 3 H) 1.48 (s, 3 H) 1.32 (d, J=6.06 Hz, 3H); LCMS for C₂₅H₂₉N₃O₄ m/z 436.20 (M+H)⁺.

Example 80 4-Benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 4-benzyloxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (77b) (6.98 g, 23.40 mmol) in CH₂Cl₂ (100 mL) was added thionyl chloride (2.04 mL, 28.1 mmol), followed by 10 drops of DMF. The mixture was refluxed for 2 h, then concentrated and dried under vacuum. The residue was dissolved in CH₂Cl₂ (100 mL), and 3-amino-1-methyl-pyrazole (2.73 g, 28.1 mmol) was added at 0° C., followed by triethylamine (6.52 ml, 46.80 mmol). The mixture was stirred at 0° C. to room temperature for 1 hr. The reaction was quenched with H₂O, extracted with 3×CH₂Cl₂. The combined organic layers were dried over Na₂SO₄, concentrated and purified by flash column chromatography with 1-3% MeOH in CHCl₃ to give a white solid (5.31 g, 60% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1 H) 7.29-7.50 (m, 6 H) 7.09 (d, J=1.01 Hz, 1 H) 6.84 (dd, J=8.08, 1.77 Hz, 2 H) 5.14 (s, 2 H) 3.83 (s, 3 H) 2.95-3.06 (m, 2 H) 1.50 (s, 6 H); LCMS for C₂₂H₂₃N₃O₃ m/z 378.20 (M+H⁺).

Example 81 2,2-Dimethyl-4-(1-pyridin-2-yl-ethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (80 mg, 0.28 mmol) and 1-pyridin-2-yl-ethanol (81a) (48 mg, 0.39 mmol) in 4 mL of THF was added PPh₃ (110 mg, 0.42 mmol) at 0° C., followed by DIAD (0.082 mL, 0.42 mmol) drop-wise. The mixture was stirred at room temperature overnight, concentrated, and purified by reverse phase HPLC to give a white solid (30 mg, 27% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.61 (br. s., 1 H) 8.79 (d, J=4.55 Hz, 1 H) 7.94-8.06 (m, 1 H) 7.69 (d, J=8.08 Hz, 1 H) 7.45-7.53 (m, 1 H) 7.27-7.31 (m, 1 H) 6.94-7.00 (m, 2 H) 6.81-6.86 (m, 1 H) 5.84 (q, J=6.40 Hz, 1 H) 3.80 (s, 3 H) 3.09 (s, 2 H) 1.70-1.77 (m, 3 H) 1.48 (d, J=4.80 Hz, 6 H); LCMS for C₂₂H₂₄N₄O₃ m/z 393.20 (M+H⁺).

Preparation of Intermediate 81a 1-Pyridin-2-yl-ethanol

To a solution of 1-(pyridin-2-yl)ethanone (1.00 g, 8.255 mmol) in 20 mL of MeOH was added NaBH₄ (625 mg, 16.5 mmol) at 0° C. The mixture was stirred at 0° C. to room temperature for 2 h, then quenched with H₂O, extracted with 3×EtOAc, dried over Na₂SO₄, and concentrated to give a colorless oil (1.00 g, 98% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (d, J=4.80 Hz, 1 H) 7.62-7.76 (m, 1 H) 7.26-7.31 (m, 1 H) 7.21 (dd, J=7.07, 4.80 Hz, 1 H) 4.90 (d, J=6.57 Hz, 1 H) 4.30 (br. s., 1 H) 1.45-1.57 (m, 3 H); LCMS for C₇H₉NO m/z 124.20 (M+H⁺).

Examples 82-87 were prepared in a similar manner as described for Example 81, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) and the appropriate alcohols.

Example 82 2,2-Dimethyl-4-(1-pyrazin-2-yl-ethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 83 2,2-Dimethyl-4-[1-(3-methyl-pyrazin-2-yl)-ethoxy]-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 84 4-(2-Methoxy-1-methyl-ethoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 85 2,2-Dimethyl-4-(1-methyl-2-morpholin-4-yl-ethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 86 2,2-Dimethyl-4-(1-pyrimidin-4-yl-ethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 87 2,2-Dimethyl-4-[1-(4-methyl-pyridin-2-yl)-ethoxy]-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example MW MF NMR m/z 82 393.5 C21H23N5O3 ¹H NMR (400 MHz, CDCl₃)) δ 8.73 (d, 394.20 (M + H⁺) J = 1.26 Hz, 1 H) 8.53-8.57 (m, 1 H) 8.51 (d, J = 2.53 Hz, 1 H) 8.39 (s, 1 H) 7.27 (s, 1 H) 6.93 (s, 1 H) 6.80 (s, 1 H) 6.77 (d, J = 2.02 Hz, 1 H) 5.61 (q, J = 6.57 Hz, 1 H) 3.80 (s, 3 H) 3.08 (s, 2 H) 1.73 (d, J = 6.57 Hz, 3 H) 1.52 (d, J = 4.80 Hz, 6 H); 83 407.5 C22H25N5O3 ¹H NMR (400 MHz, CDCl₃)) δ 408.20 (M + H⁺) 8.35-8.46 (m, 3 H) 7.26-7.31 (m, 1 H) 6.96 (s, 1 H) 6.72-6.83 (m, 2 H) 5.72 (q, J = 6.57 Hz, 1 H) 3.81 (s, 3 H) 3.01 (s, 2 H) 2.67 (s, 3 H) 1.75 (d, J = 6.57 Hz, 3 H) 1.49 (d, J = 4.80 Hz, 6 H); 84 359.4 C19H25N3O4 ¹H NMR (400 MHz, CDCl₃)) δ 8.98 (br. s., 360.20 (M + H⁺) 1 H) 7.31 (d, J = 2.27 Hz, 1 H) 7.06 (s, 1 H) 6.87 (dd, J = 4.29, 1.77 Hz, 2 H) 4.62-4.74 (m, 1 H) 3.84 (s, 3 H) 3.55-3.62 (m, 1 H) 3.48-3.53 (m, 1 H) 3.41 (s, 3 H) 2.99 (d, J = 4.04 Hz, 2 H) 1.49 (d, J = 8.84 Hz, 6 H) 1.32 (d, J = 6.32 Hz, 3 H); 85 414.5 C22H30N4O4 ¹H NMR (400 MHz, CDCl₃)) 9.60 (br. s., 1 415.20 (M + H⁺) H) 7.33 (d, J = 1.77 Hz, 1 H) 7.11 (s, 1 H) 7.00 (s, 1 H) 6.88 (s, 1 H) 5.08-5.19 (m, 1 H) 3.96-4.05 (m, 4 H) 3.85 (s, 3 H) 3.45 (dd, J = 13.64, 9.35 Hz, 2 H) 3.15-3.26 (m, 2 H) 2.89-3.01 (m, 4 H) 1.48 (d, J = 8.84 Hz, 6 H) 1.34 (d, J = 6.06 Hz, 3 H); 86 393.5 C21H23N5O3 ¹H NMR (400 MHz, CDCl₃)) δ 9.20 (d, 394.00 (M + H⁺) J = 1.26 Hz, 1 H) 8.72 (d, J = 5.05 Hz, 1 H) 8.37 (br. s., 1 H) 7.44 (dd, J = 5.05, 1.26 Hz, 1 H) 7.27 (s, 1 H) 6.86 (s, 1 H) 6.82 (s, 1 H) 6.76 (d, J = 2.27 Hz, 1 H) 5.47 (d, J = 6.57 Hz, 1 H) 3.81 (s, 3 H) 3.09 (s, 2 H) 1.69 (d, J = 6.57 Hz, 3 H) 1.53 (d, J = 4.80 Hz, 6 H); 87 406.5 C23H26N4O3 ¹H NMR (400 MHz, CDCl₃)) δ 9.79 (br. s., 407.00 (M + H⁺) 1 H) 8.80 (d, J = 5.81 Hz, 1 H) 7.62 (s, 1 H) 7.40-7.51 (m, 1 H) 7.27-7.38 (m, 1 H) 7.04 (d, J = 4.04 Hz, 2 H) 6.86 (d, J = 2.27 Hz, 1 H) 5.99 (q, J = 6.57 Hz, 1 H) 3.89 (s, 3 H) 3.12 (s, 2 H) 2.59 (s, 3 H) 1.77 (d, J = 6.32 Hz, 3 H) 1.51 (s, 6 H);

The following intermediates were prepared in a similar manner as described for Intermediate 81a from the appropriate ketones:

Intermediate Structure Name MW NMR m/z 82a

1-Pyrazin-2-yl- ethanol 124 ¹H NMR (400 MHz, CDCl₃)) δ 8.68 (s, 1 H) 8.49-8.58 (m, 2 H) 5.01 (q, J = 6.65 Hz, 1 H) 3.47 (br. s., 1 H) 1.53-1.63 (m, 3 H); 125.20 (M + H⁺) 83a

1-(3-Methyl- pyrazin-2-yl)- ethanol 138 ¹H NMR (400 MHz, CDCl₃)) δ 8.42 (d, J = 2.53 Hz, 1 H) 8.38 (d, J = 2.53 Hz, 1 H) 5.04 (s, 1 H) 4.22 (d, J = 7.83 Hz, 1 H) 2.58 (s, 3 H) 1.46 (d, J = 6.57 Hz, 3 H); 139.20 (M + H⁺) 86a

1-Pyrimidin-4- yl-ethanol 124 ¹H NMR (400 MHz, CDCl₃)) δ 9.18 (d, J = 1.26 Hz, 1 H) 8.72 (d, J = 5.30 Hz, 1 H) 7.33-7.45 (m, 1 H) 4.81-4.95 (m, 1 H) 3.69 (br. s., 1 H) 1.54 (d, J = 6.57 Hz, 3 H); 125.20 (M + H⁺) 87a

1-(4-Methyl- pyridin-2-yl)- ethanol 137 ¹H NMR (400 MHz, CDCl₃)) δ 8.39 (d, J = 5.05 Hz, 1 H) 7.09 (s, 1 H) 7.03 (d, J = 5.05 Hz, 1 H) 4.85 (d, J = 6.06 Hz, 1 H) 4.29 (br. s., 1 H) 2.38 (s, 3 H) 1.50 (d, J = 6.57 Hz, 3 H); 138.20 (M + H⁺)

Example 88 4-(6-Hydroxy-2-pyrazin-2-yl-pyrimidin-4-ylmethoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (80 mg, 0.280 mmol) and 6-(chloromethyl)-2-(pyrazin-2-yl)pyrimidin-4-ol (124 mg, 0.557 mmol) in 3 mL of DMF was added Cs₂CO₃ (181 mg, 0.557 mmol). The mixture was heated at 60° C. overnight, then filtered, washed with EtOAc, concentrated, and purified by reverse phase HPLC to give a white solid (13 mg, 10% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.67 (d, J=1.52 Hz, 1 H) 8.83 (d, J=2.53 Hz, 1 H) 8.65-8.67 (m, 1 H) 8.50 (s, 1 H) 7.27-7.31 (m, 1 H) 7.06 (d, J=1.01 Hz, 1 H) 6.88 (s, 1 H) 6.76-6.82 (m, 1 H) 6.72 (s, 1 H) 5.13 (s, 2 H) 3.81 (s, 3 H) 3.11 (s, 2 H) 1.49-1.55 (m, 6 H); LCMS for C₂₄H₂₃N₇O₄ m/z 474.00 (M+H⁺).

Example 89 4-Cyclopropylmethoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To 60 mg of cesium carbonate (180 μmol) in a test tube (10×95 mm) was added 0.8 mL of 0.1 M solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) in acetonitrile followed by 1 mL of 0.1 M solution of chloromethyl cyclopropane in acetonitrile and the reaction was stirred at 80° C. for 8 h. After the removal of solid cesium carbonate, the acetonitrile was removed, the residue was reconstituted in 1.2 mL of DMSO and subjected to HPLC purification to obtain the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 10.56 (s, 1 H) 7.57 (s, 1 H) 6.92 (s, 1 H) 6.54 (s, 1 H) 3.92-3.93 (d, J=5.00 Hz, 2 H) 2.94 (s, 2 H) 1.42 (s, 6 H) 0.55-0.60 (m, 2 H) 0.30-0.35 (m, 1H); LCMS for C₁₉H₂₃N₃O₃ m/z 342 (M+H)⁺.

Examples 90-106 were prepared in parallel in a similar manner as described for Example 89, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) and the appropriate alkylating reagents.

Example 90 2,2-Dimethyl-4-(2-methyl-thiazol-4-ylmethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 91 4-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 92 4-Ethoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 93 4-(3-Cyano-propoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 94 2,2-Dimethyl-4-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 95 4-(2-Cyclopropyl-6-hydroxy-pyrimidin-4-ylmethoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 96 2,2-Dimethyl-4-(5-methyl-[1,2,4]oxadiazol-3-ylmethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 97 4-[2-(4-Hydroxymethyl-phenyl)-2-oxo-ethoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 98 2,2-Dimethyl-4-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 99 2,2-Dimethyl-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 100 2,2-Dimethyl-4-(3-propyl-[1,2,4]oxadiazol-5-ylmethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 101 4-(3-Methoxy-butoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 102 4-((S)-3-Hydroxy-2-methyl-propoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 103 2,2-Dimethyl-4-[2-(6-methyl-pyridin-3-yl)-2-oxo-ethoxy]-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 104 4-(2-Ethyl-6-hydroxy-pyrimidin-4-ylmethoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 105 2,2-Dimethyl-4-[2-(1-methyl-1H-pyrazol-4-yl)-2-oxo-ethoxy]-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 106 2,2-Dimethyl-4-(2-methyl-pyridin-3-ylmethoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example MW MF NMR m/z 90 398.5 C20H22N4O3S ¹H NMR (500 MHz,, DMSO-d₆)) δ 399 (M + H)⁺ 10.60 (s, 1 H) 7.58 (s, 1 H) 7.50 (s, 1H) 7.28 (s, 1 H) 6.95 (s, 1H) 6.55 (s, 1 H) 5.21 (s, 2 H) 2.95 (s, 2 H) 1.40-1.44 (m, 9 H); 91 425.5 C22H27N5O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 426 (M + H)⁺ 10.59 (s, 1 H) 7.58 (s, 1 H) 7.30 (s, 1 H) 6.98 (s, 1H) 6.55 (s, 1 H) 6.39 (s, 2 H) 2.95 (s, 2 H) 1.37-1.44 (m, 15 H); 92 315.4 C17H21N3O3 ¹H NMR (500 MHz,, DMSO-d₆)) δ 316 (M + H)⁺ 10.58 (s, 1 H) 7.57 (s, 1 H) 7.12 (s, 1H) 6.92 (s, 1H) 6.54 (s, 1 H) 4.10-4.15 (m, 2 H) 2.92 (s, 2 H) 1.42 (m, 6 H) 1.32-1.36 (m, 3H); 93 354.4 C19H22N4O3 ¹H NMR (500 MHz,, DMSO-d₆)) δ 355 (M + H)⁺ 10.60 (s, 1 H) 7.57 (s, 1 H) 7.14 (s, 1 H) 6.95 (s, 1 H) 6.55 (s, 1 H) 4.15 (s, 2 H) 2.96 (s, 2 H) 2.00-2.10 (m, 2 H) 1.42 (m, 6 H); 94 383.4 C19H21N5O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 384 (M + H)⁺ 10.59 (s, 1 H) 7.57 (s, 1 H) 7.25 (s, 1 H), 7.00 (s, 1H) 6.55 (s, 1 H) 5.56 (s, 2 H) 2.98 (s, 2 H) 2.36 (s, 3 H) 1.43 (m, 6 H); 95 435.5 C23H25N5O4 ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1 H) 436 (M + H)⁺ 7.20-7.34 (m, 1 H) 6.97 (s, 1 H) 6.86 (s, 1 H) 6.81 (d, J = 2.27 Hz, 1 H) 6.43 (s, 1 H) 4.92 (s, 2 H) 3.82 (s, 3 H) 3.06 (s, 2 H) 1.83-1.95 (m, 1 H) 1.46-1.54 (m, 6 H) 1.19-1.28 (m, 2 H) 1.07-1.16 (m, 2 H); 96 383.4 C19H21N5O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 384 (M + H)⁺ 10.60 (s, 1 H) 7.58 (s, 1H), 7.28 (s, 1 H) 6.97 (s, 1 H) 6.55 (s, 1 H) 5.34 (s, 2H) 2.94 (s, 2 H) 2.36 (s, 3 H) 1.42 (s, 6 H); 97 435.5 C24H25N3O5 ¹H NMR (500 MHz,, DMSO-d₆)) δ 436 (M + H)⁺ 10.49 (s, 1 H) 7.98-7.99 (m, 2 H) 7.55 (s, 1 H), 7.51-7.52 (m, 2 H) 7.03 (s, 1H) 6.95 (s, 1 H) 6.51 (s, 1 H) 5.64 (s, 2 H) 5.44-5.45 (m, 1 H) 4.60-4.62 (m, 2 H) 3.00 (s, 2 H) 2.36 (s, 3 H) 1.44 (m, 6 H); 98 446.5 C23H22N6O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 447 (M + H)⁺ 10.60 (s, 1 H) 7.99-8.10 (m, 2 H), 7.55-7.65 (m, 2 H) 7.30-6.97 (s, 1 H) 6.55 (s, 1 H) 5.70 (s, 2 H) 3.03 (s, 2 H) 1.44 (s, 6 H); 99 412.5 C21H24N4O3S ¹H NMR (500 MHz,, DMSO-d₆)) δ 413 (M + H)⁺ 10.59 (s, 1 H) 8.82 (s, 1 H), 7.57 (s, 1 H) 7.13 (s, 1 H) 6.92 (s, 1 H) 6.54 (s, 1 H) 4.25 (s, 2 H) 2.91 (s, 2 H) 2.36 (s, 3 H) 1.42 (s, 6 H); 100 411.5 C21H25N5O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 412 (M + H)⁺ 10.58 (s, 1 H) 7.57 (s, 1 H) 7.24 (s, 1 H) 7.00 (s, 1 H) 6.55 (s, 1 H) 5.56 (s, 2 H) 2.98 (s, 2 H) 2.67-2.72 (m, 2 H) 1.63-1.72 (m, 2 H) 1.43 (s, 6 H) 0.86-0.91 (m, 3 H); 101 373.5 C20H27N3O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 374 (M + H)⁺ 10.59 (s, 1 H) 7.57 (s, 1 H) 7.12 (s, 1 H) 6.92 (s, 1 H) 6.54 (s, 1 H) 4.09-4.15 (m, 2 H) 3.20-3.25 (m, 1 H) 2.92 (s, 2 H) 1.82-1.90 (m, 2 H) 1.42 (br s, 8 H) 1.14-1.15 (d, J = 10 Hz, 3 H); 102 359.4 C19H25N3O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 360 (M + H)⁺ 10.58 (s, 1 H) 7.57 (s, 1 H) 7.12 (s, 1 H) 6.92 (s, 1 H) 6.54 (s, 1 H) 3.9-4.1 (m, 1 H) 3.88-3.92 (m, 1 H) 2.93 (s, 2 H) 1.97-2.02 (m, 1 H) 1.42 (br s, 8 H) 0.96-0.98 (d, J = 10 Hz, 3 H); 103 420.5 C23H24N4O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 421 (M + H)⁺ 10.48 (s, 1 H) 9.05 (s, 1 H) 8.21-8.23 (d, J = 10 Hz, 1 H), 7.55 (s, 1 H) 7.46-7.48 (d, J = 10 Hz, 1 H) 7.06 (s, 1 H) 6.95 (s, 1 H) 6.54 (s, 1 H) 5.65 (s, 2 H) 3.00 (s, 2 H) 1.82-1.90 (m, 2 H) 1.44 (s, 6 H); 104 423.5 C22H25N5O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 424 (M + H)⁺ 10.63 (s, 1 H) 7.57 (s, 1 H) 7.21 (s, 1 H) 6.96 (s, 1 H) 6.54 (s, 1 H) 6.18 (s, 1 H) 5.01 (s, 2 H) 3.04 (s, 2 H) 1.44 (s, 6 H) 1.15-1.25 (m, 3 H); 105 409.4 C21H23N5O4 ¹H NMR (500 MHz,, DMSO-d₆)) δ 410 (M + H)⁺ 10.51 (s, 1 H) 8.45 (s, 1 H) 8.03 (s, 1 H) 7.56 (s, 1 H) 7.00 (s, 1 H) 6.95 (s, 1 H) 6.52 (s, 1 H) 5.26 (s, 2 H) 3.90 (s, 3 H) 3.02 (s, 2 H) 1.44 (s, 6 H); 106 392.5 C22H24N4O3 ¹H NMR (500 MHz,, DMSO-d₆)) δ 393 (M + H)⁺ 10.59 (s, 1 H) 8.40 (s, 1 H) 7.80-8.03 (m, 1 H) 7.58 (s, 1 H) 7.25-7.30 (m, 2 H) 6.97 (s, 1 H) 6.55 (s, 1 H) 5.22 (s, 2 H) 2.96 (s, 2 H) 1.42 (s, 9 H);

Examples 107-111 were prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) and the corresponding fluorophenyl amide intermediates. The appropriate fluorophenyl amide intermediates were prepared in a similar manner as described for Intermediate 32a, 33a, or 35a, from the appropriate carboxylic acids or acid chlorides and amines.

Example 112 was prepared in a similar manner as described for Example 1, from 4-(4-ethylcarbamoyl-3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (112b).

Preparation of Intermediate 112a 4-(4-tert-Butoxycarbonyl-3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) and 4-bromo-2,6-difluoro-benzoic acid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1 H) 7.23 (s, 1 H) 6.48 (d, J=8.84 Hz, 2 H) 3.89 (s, 3 H) 2.88 (s, 2 H) 1.59 (s, 9 H) 1.49 (s, 6 H); LCMS for C₂₃H₂₄F₂O₆ m/z 457.20 (M+Na)⁺.

Preparation of Intermediate 112b 4-(4-Ethylcarbamoyl-3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

TFA (2 mL) was added to a solution of 4-(4-tert-butoxycarbonyl-3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (870 mg, 2.00 mmol) in CH₂Cl₂ (8 mL). The mixture was stirred at room temperature for 2 hr, concentrated in vacuo, and dried to give an off-white solid (TFA salt) (735 mg, 75% yield). The solid was then dissolved in DMF (3 mL) and added Et₃N (320 uL, 2.30 mmol), HATU (425 mg, 1.12 mmol) and ethyl amine (600 uL, 1.2 mmol). The mixture was stirred at room temperature for 1 hr, quenched with H₂O (30 mL), and extracted with EtOAc (2×30 mL). The organic layers were washed with H₂O (2×50 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 80% EtOAc in hexanes to give an off-white solid (213 mg, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, J=1.13 Hz, 1 H) 6.50 (d, J=9.04 Hz, 2 H) 3.89 (s, 3 H) 3.50 (dd, J=7.25, 5.75 Hz, 2 H) 2.88 (s, 2 H) 2.86 (d, J=3.77 Hz, 1 H) 1.48 (s, 6 H) 1.25 (t, J=7.25 Hz, 3 H).

Example 107 4-(2-Chloro-4-dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 108 4-(3-Chloro-4-dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 109 4-(4-Dimethylcarbamoyl-2,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 110 4-[4-(Azetidine-1-carbonyl)-3,5-difluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 111 4-(4-Dimethylcarbamoyl-3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 112 4-(4-Ethylcarbamoyl-3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example MW MF NMR m/z Elemental Analysis 107 468.9 C24H25ClN4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.81 (s, 1 H) 469.00 (M + H)⁺ Calcd. for C₂₄H₂₅ClN₄O₄•0.56 7.57 (d, J = 2.02 Hz, 1 H) 7.30 (dd, J = 8.34, AcOH: C, 60.03; H, 2.02 Hz, 1 H) 7.28 (s, 1 H) 7.07 (d, J = 1.26 5.47; N, 11.15; Found: C, Hz, 1 H) 6.98 (d, J = 1.26 Hz, 1 H) 6.96 (d, 60.03; H, 5.37; N, 11.34 J = 8.34 Hz, 1 H) 6.79 (d, J = 2.27 Hz, 1 H) 3.80 (s, 3 H) 3.10 (s, 3 H) 3.06 (s, 3 H) 2.96 (s, 2 H) 1.51 (s, 6 H); 108 468.9 C24H25ClN4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1 H) 469.00 (M + H)⁺ Calcd. for C₂₄H₂₅ClN₄O₄•0.76 7.29 (d, J = 2.27 Hz, 1 H) 7.25 (s, 1 H) 7.10 AcOH: C, 59.57; H, (dd, J = 9.09, 1.26 Hz, 2 H) 7.00 (d, J = 2.27 5.49; N, 10.89; Found: C, Hz, 1 H) 6.91 (dd, J = 8.46, 2.40 Hz, 1 H) 59.33; H, 5.23; N, 11.10. 6.80 (d, J = 2.02 Hz, 1 H) 3.82 (s, 3 H) 3.14 (s, 3 H) 2.92 (s, 3 H) 2.90 (s, 2 H) 1.50 (s, 6 H); 109 470.5 C24H24F2N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1 H) 471.00 (M + H)⁺ Calcd. for C₂₄H₂₄F₂N₄O₄•0.53 7.24-7.29 (m, 2 H) 7.08 (s, 1 H) 7.03 (s, AcOH: C, 59.92; H, 1 H) 6.79 (d, J = 2.02 Hz, 1 H) 6.73 (dd, 5.24; N, 11.15; Found: C, J = 9.47, 6.44 Hz, 1 H) 3.81 (s, 3 H) 59.92; H, 5.14; N, 11.12. 3.13 (s, 3 H) 2.95-3.01 (m, 5 H) 1.52 (s, 6 H); 110 482.5 C25H24F2N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1 H) 483.00 (M + H)⁺ Calcd. for C₂₅H₂₄F₂N₄O₄•0.36 7.29 (d, J = 2.02 Hz, 1 H) 7.04-7.11 (m, 2 AcOH: C, 61.28; H, H) 6.80 (d, J = 2.27 Hz, 1 H) 6.52 (d, 5.09; N, 11.11; Found: C, J = 8.59 Hz, 1 H) 4.02-4.28 (m, 4 H) 61.29; H, 5.07; N, 11.12. 3.82 (s, 3 H) 2.88 (s, 2 H) 2.34 (ddd, J = 15.79, 8.08, 7.96 Hz, 2 H) 1.50 (s, 6 H); 111 470.5 C24H24F2N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1 H) 471.00 (M + H)⁺ Calcd. for C₂₄H₂₄F₂N₄O₄•0.33 7.29 (s, 1 H) 7.08 (s, 2 H) 6.78 (d, J = 2.02 Hz, H2O: C, 60.51; H, 1 H) 6.53 (d, J = 8.08 Hz, 2 H) 3.82 (s, 5.22; N, 11.76; Found: C, 3 H) 3.15 (s, 3 H) 2.99 (s, 3 H) 2.90 (s, 2 60.51; H, 5.37; N, 11.67 H) 1.50 (s, 6 H); 112 470.5 C24H24F2N4O4 ¹H NMR (400 MHz, CDCl₃) δ 8.96 (br. s., 1 471.20 (M + H)⁺ Calcd. for C₂₄H₂₄F₂N₄O₄•1.14 H) 7.12 (s, 1 H) 7.03 (s, 1 H) 6.76 (s, 1 H) H₂O•0.63 EtOAc: C, 6.50 (d, J = 8.84 Hz, 2 H) 6.26-6.42 (m, 1 58.28; H, 5.78; N, 10.25; H) 3.76 (s, 3 H) 3.46-3.55 (m, 2 H) Found: C, 58.28; H, 5.62; N, 2.91 (s, 2 H) 1.50 (s, 6 H) 1.28 (t, J = 6.69 10.26. Hz, 3 H);

Example 113 4-(3,5-Difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a mixture of 4-(3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (113b) (0.308 g, 0.00096 mol), EDCl (0.28 g, 0.0015 mol), HOBt (0.21 g, 0.0015 mol) and NMM (0.49 g, 0.0048 mol) in CH₂Cl₂ (15 mL) was added 1-methyl-1H-pyrazol-3-amine (0.11 g, 0.001 mol) in one portion. The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, aq. citric acid and then sat. NaHCO₃. The organic phase was dried over Na₂SO₄ and concentrated to give a brown oil. The crude oil was purified by prep. HPLC to give the title compound (95 mg, 51% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.82 (s, 1H), 7.20 (m, 2H), 7.03 (d, 2H), 6.73 (s, 1H), 6.42 (m, 3H), 3.72 (s, 3H), 2.84 (s, 2H), 1.42 (s, 6H);

LCMS for C₂₁H₁₉F₂N₃O₃ m/z 400.4 (M+H)⁺.

Preparation of Intermediate 113a 4-(3,5-Difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

A mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxy-lic acid methyl ester (3e) (1 g, 0.0045 mol), 3,5-difluorophenylboronic acid (1.07 g, 0.0068 mol), Cu(OAc)₂ (0.9 g, 0.005 mol), freshly activated 4 Å molecular sieves (4 g) and Et₃N (4 mL) in CH₂Cl₂ (25 mL) was stirred at room temperature under N₂ for 48 hrs. The mixture was filtered through Celite and the filter cake was washed with CH₂Cl₂. The filtrate was concentrated to give a dark liquid. The crude liquid was purified by column chromatography eluting with EtOAc/petroleum ether (1/5) to give the title compound (0.4 g, 26.6%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.18 (s, 1H), δ 7.14 (s, 1H), 6.47(m, 1H), δ 6.36 (dd, 2H), 3.81 (s, 3H), 2.83 (s, 2H), 1.41 (s, 6H).

Preparation of Intermediate 113b 4-(3,5-Difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid

To a solution of 4-(3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (113a) (0.4 g, 0.0012 mol) in MeOH (5 mL) was added NaOH (0.5 g, 0.012 mol) in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/10) showed the starting material was still present. The mixture was refluxed for another 3 hrs. After TLC indicated the reaction was complete. The solvents were removed in vacuo. The residue was dissolved in water and acidified with conc. HCl to pH 1. The aqueous phase was extracted with EtOAc (2×15 mL). The organic phase was dried over Na₂SO₄ and concentrated to give an off-white solid (0.308 g, 80% yield).

Example 114 4-(3-Fluoro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and Example 115 4-(5-Fluoro-2-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

A mixture of 2,4-difluorophenyl methyl sulfone (67 mg, 0.35 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (100 mg, 0.35 mmol), and Cs₂CO₃ (227 mg, 0.70 mmol) in DMF (2 mL) was heated to 120° C. overnight, then cooled to room temperature, quenched with H₂O (50 mL), and extracted with EtOAc (2×50 mL). The organic layers were washed with H₂O (2×80 mL), dried over Na₂SO₄ and concentrated. The residue was purified by SFC column chromatography to give Example 114 (49 mg, 31% yield) and Example 115 (15 mg) as white solids.

Example 114: ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1 H) 7.92 (t, J=8.46 Hz, 1 H) 7.29 (d, J=2.27 Hz, 1 H) 7.09 (d, J=7.58 Hz, 2 H) 6.88 (dd, J=8.72, 2.15 Hz, 1 H) 6.76-6.83 (m, 2 H) 3.82 (s, 3 H) 3.23 (s, 3 H) 2.90 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₂H₂₂FN₃O₅S m/z 460.20 (M+H)⁺;

Example 115: ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H) 8.09 (dd, J=8.84, 6.06 Hz, 1 H) 7.26-7.34 (m, 1 H) 7.14 (d, J=18.44 Hz, 2 H) 6.89-6.97 (m, 1 H) 6.79 (d, J=2.27 Hz, 1 H) 6.60 (dd, J=9.60, 2.27 Hz, 1 H) 3.81 (s, 3 H) 3.30 (s, 3 H) 2.92 (s, 2 H) 1.49 (s, 6H); LCMS for C₂₂H₂₂FN₃O₅S m/z 460.20 (M+H)⁺.

Example 116 4-(3-Fluoro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (116a) (233 mg, 0.591 mmol) to give a white solid (140 mg, 50% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1 H) 8.22 (d, J=8.59 Hz, 1 H) 8.11 (d, J=2.27 Hz, 1 H) 7.86-8.00 (m, 1 H) 7.57 (dd, J=8.46, 2.15 Hz, 1 H) 7.14 (dd, J=18.95, 1.52 Hz, 2 H) 6.71-6.92 (m, 2 H) 3.23 (s, 3 H) 2.90 (s, 2 H) 2.32 (s, 3 H) 1.51 (s, 6 H); LCMS for C₂₄H₂₃FN₂O₅S m/z 471.20 (M+H⁺); Anal. Calcd. for C₂₄H₂₃FN₂O₅S: C, 61.27; H, 4.93; N, 5.95; Found: C, 61.55; H, 4.86; N, 5.99.

Preparation of Intermediate 116a 4-(3-Fluoro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

A mixture of 2,4-difluorophenyl methyl sulfone (865 mg, 4.50 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.00 g, 4.50 mmol), and Cs₂CO₃ (2.93 g, 9.00 mmol) in DMF (2 mL) was heated to 80° C. for 2.5 h, cooled to room temperature, quenched with H₂O and extracted with 3×EtOAc. The organic layers were washed with 2×H₂O, dried over Na₂SO₄ and concentrated. The residue was purified by Biotage column chromatography with 15%-40% EtOAc in hexanes to give a white solid (1.20 g, 68% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.95 (m, 1 H) 7.21-7.34 (m, 2 H) 6.72-6.88 (m, 2 H) 3.90 (s, 3 H) 3.22 (s, 3 H) 2.90 (s, 2 H) 1.48 (s, 6 H); LCMS for C₁₉H₁₉FO₆S m/z 395.00 (M+H)⁺.

Example 117 4-(3-Fluoro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1 from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (116a) (146 mg, 0.37 mmol) to give a white solid (87 mg, 51% yield). ¹H NMR (300 MHz, CD₃OD) δ 7.93-7.98 (m, 1 H) 7.90 (d, J=3.96 Hz, 1 H) 7.18-7.25 (m, 1 H) 7.14-7.27 (m, 1 H) 6.86-7.07 (m, 2 H) 4.09 (d, J=0.94 Hz, 3 H) 3.23 (s, 3 H) 2.93 (s, 2 H) 1.48 (s, 6 H); LCMS for C₂₁H₂₁FN₄O₅S m/z 461.00 (M+H⁺); Anal. Calcd. for C₂₁H₂₁FN₄O₅S: C, 54.78; H, 4.60; N, 12.17; Found: C, 54.64; H, 4.55; N, 12.10.

Example 118 4-(3-Chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1 from 4-(3-chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (118a) (154 mg, 0.370 mmol) to give a white solid (154 mg, 87% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1 H) 8.08 (s, 2 H) 7.70-7.86 (m, 1H) 6.89-7.14 (m, 3H) 4.12 (s, 3 H) 3.11 (s, 3 H) 2.96 (s, 2 H) 1.53 (s, 6H); LCMS for C₂₁H₂₁ClN₄O₅S m/z 477.00 and 479.00 (M+H⁺); Anal. Calcd. for C₂₁H₂₁ClN₄O₅S.0.15CHCl₃: C, 51.33; H, 4.31; N, 11.32; Found: C, 51.16; H, 4.35; N, 11.47.

Preparation of Intermediate 118a 4-(3-Chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

A mixture of 2-chloro-4-fluoro-1-(methylsulfonyl)benzene (939 mg, 4.50 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.00 g, 4.50 mmol) and Cs₂CO₃ (2.93 g, 9.00 mmol) in DMF (5 mL) was heated to 80° C. for 1.5 h, cooled to room temperature, quenched with H₂O and extracted with 3×EtOAc. The organic layers were washed with 2×H₂O, dried over Na₂SO₄ and concentrated. The residue was purified by Biotage column chromatography with 25-50% EtOAc in hexanes to give a white solid (1.70 g, 92% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=8.84 Hz, 1H) 7.31 (d, J=1.26 Hz, 1 H) 7.25 (d, J=1.26 Hz, 1 H) 7.10 (d, J=2.27 Hz, 1 H) 6.88-7.03 (m, 1 H) 3.89 (s, 3 H) 3.28 (s, 3 H) 2.88 (s, 2 H) 1.50 (s, 6 H); LCMS for C₁₉H₁₉ClO₆S m/z 411.00 and 413.00 (M+H)⁺.

Example 119 4-(2-Chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

To a solution of 4-(2-chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (119b) (138 mg, 0.348 mmol), 2-methyl-2H-1,2,3-triazol-4-amine hydrochloride (93.6 mg, 0.695 mmol) and triethylamine (0.145 mL, 1.040 mmol) in 2 mL of DMF was added HATU (264 mg, 0.695 mmol). The mixture was stirred at 50° C. for 1.5 h, and purified by reverse phase column chromatography to give a white solid (100 mg, 60% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1 H) 8.00-8.08 (m, 2 H) 7.05-7.17 (m, 3 H) 6.95 (dd, J=8.84, 2.53 Hz, 1 H) 4.07 (s, 3 H) 3.26 (s, 3 H) 2.88 (s, 2 H) 1.48 (s, 6 H); LCMS for C₂₁H₂₁ClN₄O₅S m/z 476.8, 477.80, and 478.70 (M+H⁺); Anal. Calcd. for C₂₁H₂₁ClN₄O₅S.0.65 TFA: C, 48.61; H, 3.96; N, 10.17; Found: C, 48.41; H, 4.07; N, 10.51.

Preparation of Intermediate 119a 4-(2-Chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 118a, from 3-chloro-4-fluoro-1-(methylsulfonyl)benzene and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e). ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=2.27 Hz, 1 H) 7.77 (dd, J=8.59, 2.27 Hz, 1 H) 7.29 (d, J=1.01 Hz, 1 H) 7.18 (d, J=1.26 Hz, 1 H) 6.98 (d, J=8.59 Hz, 1 H) 3.88 (s, 3 H) 3.10 (s, 3 H) 2.93 (s, 2 H) 1.50 (s, 6 H); LCMS for C₁₉H₁₉ClO₆S m/z 411.00 (M+H)⁺.

Preparation of Intermediate 119b 4-(2-Chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid

The title compound was prepared in a similar manner as described for Intermediate 15a, from 4-(2-chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (119a). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=2.27 Hz, 1 H) 7.78 (dd, J=8.59, 2.27 Hz, 1 H) 7.34 (d, J=1.26 Hz, 1 H) 7.23 (d, J=1.26 Hz, 1 H) 7.00 (d, J=8.59 Hz, 1 H) 3.11 (s, 3 H) 2.95 (s, 2 H) 1.52 (s, 6 H); LCMS for C₁₈H₁₇ClO₆S m/z 397.00 (M+H)⁺.

Examples 120, 121, 124-130, 139-141 were prepared in a similar manner as described for Example 1, from the corresponding methyl ester intermediates and the appropriate amino heterocycles.

Examples 122 and 123 were prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) and the appropriate fluorophenyl intermediates.

Examples 131-138 were prepared in a similar manner as described for Example 15, from the corresponding carboxylic acid intermediates and the appropriate amino heterocycles. The appropriate carboxylic acid intermediates were prepared in a similar manner as described for Intermediate 35c, from the corresponding methyl ester intermediates.

Example 120 4-(2-Fluoro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

Example 121 4-(2-Fluoro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 122 4-(4-Dimethylsulfamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 123 4-(4-Cyclobutanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 124 4-[4-(Azetidine-1-sulfonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

Example 125 4-[4-(Azetidine-1-sulfonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 126 4-(4-Ethanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

Example 127 4-(4-Ethanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 128 4-(4-Dimethylsulfamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

Example 129 4-(4-Cyclopropanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 130 4-(4-Dimethylsulfamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 131 4-(4-Cyclopropanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 132 4-(4-Dimethylsulfamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 133 4-(4-Ethanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 134 4-(4-Dimethylsulfamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 135 4-(4-Ethanesulfonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 136 4-(4-Ethanesulfonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 137 4-(2-Chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 138 4-(4-Dimethylsulfamoyl-2,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 139 4-(3-Chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example 140 4-(4-Cyclopropanesulfonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 141 4-(4-Cyclopropanesulfonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

Example MW MF NMR m/z Elemental Analysis 120 470.5 C24H23FN2O5S ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1 H) 471.00 (M + H)⁺ Calcd. for C₂₄H₂₃FN₂O₅S•0.23 8.21 (d, J = 8.59 Hz, 1 H) 8.11 (s, 1 H) H₂O: C, 60.73; H, 4.98; 7.80 (dd, J = 9.60, 2.02 Hz, 1 H) 7.70 (d, J = 8.59 Hz, 1 N, 5.90; Found: C, 60.74; H, H) 7.56 (dd, J = 8.59, 2.02 Hz, 1 H) 4.93; N, 5.91. 7.09-7.15 (m, 2 H) 7.03 (s, 1 H) 3.11 (s, 3 H) 2.99 (s, 2 H) 2.32 (s, 3 H) 1.53 (s, 6 H); 121 459.5 C22H22FN3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1 H) 460.00 (M + H)⁺ Calcd. for C₂₂H₂₂FN₃O₅S•0.44 7.79 (dd, J = 9.60, 2.27 Hz, 1 H) H₂O: C, 56.53; H, 4.93; 7.68-7.72 (m, 1 H) 7.28 (d, J = 2.27 Hz, 1 H) N, 8.99; Found: C, 56.53; H, 7.10-7.16 (m, 1 H) 7.04 (s, 1 H) 6.98 (s, 1 H) 4.87; N, 8.81 6.76 (d, J = 2.27 Hz, 1 H) 3.80 (s, 3 H) 3.11 (s, 3 H) 2.99 (s, 2 H) 1.52 (s, 6 H); 122 470.6 C23H26N4O5S ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1 H) 471.00 (M + H)⁺ Calcd. for C₂₃H₂₆N₄O₅S•0.54 7.73-7.78 (m, 2 H) 7.29 (d, J = 2.27 Hz, 1 AcOH: C, 57.54; H, H) 7.13 (s, 2 H) 7.07-7.11 (m, 2 H) 5.56; N, 11.11; Found: C, 6.81 (d, J = 2.27 Hz, 1 H) 3.81 (s, 3 H) 2.90 (s, 2 57.50; H, 5.64; N, 11.14. H) 2.74 (s, 6 H) 1.50 (s, 6 H); 123 481.6 C25H27N3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1 H) 482.00 (M + H)⁺ Calcd. for C₂₅H₂₇N₃O₅S•0.46 7.84 (ddd, J = 9.22, 2.78, 2.40 Hz, 2 H) H₂O: C, 61.30; H, 7.29 (d, J = 2.27 Hz, 1 H) 7.05-7.09 (m, 4 5.74; N, 8.58; Found: C, H) 6.78 (d, J = 2.27 Hz, 1 H) 3.81 (s, 3 H) 61.30; H, 5.43; N, 8.30. 2.89 (s, 2 H) 2.53-2.63 (m, 2 H) 2.18-2.27 (m, 2 H) 1.97-2.05 (m, 2 H) 1.50 (s, 6 H); 124 493.6 C26H27N3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1 H) 494.00 (M + H)⁺ Calcd. for C₂₆H₂₇N₃O₅S•0.1 8.22 (d, J = 8.59 Hz, 1 H) 8.11 (d, J = 2.27 Hz, EtOAc: C, 63.25; H, 5.38; 1 H) 7.81-7.85 (m, 2 H) 7.57 (dd, N, 8.17; Found: C, 63.12; H, J = 8.46, 2.15 Hz, 1 H) 7.11-7.14 (m, 3 H) 5.58; N, 8.36. 7.09-7.11 (m, 1 H) 3.82 (t, J = 7.71 Hz, 4 H) 2.91 (s, 2 H) 2.32 (s, 3 H) 2.09-2.18 (m, 2 H) 1.51 (s, 6 H); 125 482.6 C24H26N4O5S ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1 H) 483.00 (M + H)⁺ Calcd. for C₂₄H₂₆N₄O₅S•0.24 7.80-7.85 (m, 2 H) 7.29 (d, J = 2.02 Hz, 1 EtOAc: C, 59.49; H, H) 7.10-7.13 (m, 1 H) 7.10 (d, J = 1.77 Hz, 5.40; N, 11.12; Found: C, 2 H) 7.07 (s, 1 H) 6.78 (d, J = 2.27 Hz, 1 H) 59.49; H, 5.40; N, 11.12. 3.79-3.84 (m, 7 H) 2.91 (s, 2 H) 2.09-2.18 (m, 2 H) 1.50 (s, 6 H); 126 466.6 C25H26N2O5S ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1 H) 467.00 (M + H)⁺ Calcd. for C₂₅H₂₆N₂O₅S•0.11 8.22 (d, J = 8.34 Hz, 1 H) 8.11 (d, J = 2.27 Hz, H2O: C, 64.09; H, 1 H) 7.88 (ddd, J = 9.22, 2.78, 2.40 Hz, 5.59; N, 5.92; Found: C, 2 H) 7.57 (dd, J = 8.46, 2.15 Hz, 1 H) 64.09; H, 5.59; N, 5.92. 7.14 (d, J = 1.26 Hz, 1 H) 7.08-7.12 (m, 3 H) 3.14 (q, J = 7.33 Hz, 2 H) 2.90 (s, 2 H) 2.32 (s, 3 H) 1.50 (s, 6 H) 1.32 (t, J = 7.45 Hz, 3 H); 127 455.5 C23H25N3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H) 456.00 (M + H)⁺ Calcd. for C₂₃H₂₅N₃O₅S•0.25 7.85-7.90 (m, 2 H) 7.29 (d, J = 2.27 Hz, 1 H₂O: C, 60.10; H, H) 7.11 (s, 1 H) 7.09 (s, 1 H) 7.07 (d, 5.55; N, 8.95; Found: C, J = 2.53 Hz, 2 H) 6.78 (d, J = 2.27 Hz, 1 H) 60.05; H, 5.59; N, 9.13. 3.81 (s, 3 H) 3.14 (q, J = 7.33 Hz, 2 H) 2.90 (s, 2 H) 1.50 (s, 6 H) 1.32 (t, J = 7.45 Hz, 3 H); 128 481.6 C25H27N3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1 H) 482.00 (M + H)⁺ Calcd. for C₂₅H₂₇N₃O₅S•0.12 8.22 (d, J = 8.34 Hz, 1 H) 8.11 (d, J = 2.02 Hz, EtOAc: C, 62.19; H, 1 H) 7.74-7.79 (m, 2 H) 7.57 (dd, 5.73; N, 8.54; Found: C, J = 8.46, 2.15 Hz, 1 H) 7.12 (dd, J = 10.61, 62.24; H, 5.67; N, 8.48. 1.26 Hz, 2 H) 7.07-7.10 (m, 2 H) 2.90 (s, 2 H) 2.74 (s, 6 H) 2.32 (s, 3 H) 1.51 (s, 6 H); 129 467.5 C24H25N3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H) 468.00 (M + H)⁺ Calcd. for C₂₄H₂₅N₃O₅S•0.16 7.87 (d, J = 8.84 Hz, 2 H) 7.28 (d, J = 2.27 Hz, H2O: C, 61.28; H, 1 H) 7.10 (s, 1 H) 7.08 (s, 1 H) 5.43; N, 8.93; Found: C, 7.06 (d, J = 1.26 Hz, 2 H) 6.78 (d, J = 2.02 Hz, 1 61.23; H, 5.29; N, 8.77. H) 3.81 (s, 3 H) 2.91 (s, 2 H) 2.49 (ddd, J = 12.76, 7.96, 4.80 Hz, 1 H) 1.50 (s, 6 H) 1.36 (dt, J = 6.76, 4.71 Hz, 2 H) 1.03-1.11 (m, 2 H); 130 488.5 C23H25FN4O5S ¹H NMR (400 MHz, CDCl₃) δ 10.17 (s, 1 489.00 (M + H)⁺ Calcd. for C₂₃H₂₅FN₄O₅S: C, H) 7.81 (t, J = 8.21 Hz, 1 H) 7.48 (s, 1 H) 56.55; H, 5.16; N, 11.47; 7.24 (s, 1 H) 7.02 (s, 1 H) 6.83 (d, J = 8.84 Hz, Found: C, 56.65; H, 5.11; N, 1 H) 6.75-6.80 (m, 1 H) 4.00 (s, 3 H) 11.27. 2.90 (s, 2 H) 2.85 (d, J = 1.26 Hz, 6 H) 1.49 (s, 6 H); 131 468.5 C23H24N4O5S ¹H NMR (400 MHz, CD₃OD) δ 7.93 (s, 1 469.10 (M + H)⁺ Calcd. for C₂₃H₂₄N₄O₅S•1.05 H) 7.90-7.92 (m, 1 H) 7.88-7.90 (m, 1 H2O: C, 56.67; H, H) 7.18 (d, J = 1.77 Hz, 2 H) 7.17 (d, 5.40; N, 11.49; Found: C, J = 2.27 Hz, 2 H) 4.08 (s, 3 H) 2.91 (s, 2 H) 56.68; H, 5.18; N, 11.36. 2.63-2.70 (m, 1 H) 1.47 (s, 6 H) 1.22 (ddd, J = 7.01, 4.48, 4.17 Hz, 2 H) 1.02-1.12 (m, 2 H); 132 489.5 C22H24FN5O5S ¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 490.00 (M + H)⁺ Calcd. for C₂₂H₂₄FN₅O₅S: C, 1 H) 7.95 (s, 1 H) 7.78 (t, J = 8.46 Hz, 1 H) 53.98; H, 4.94; N, 14.31; 7.31 (s, 1 H) 7.29 (s, 1 H) 7.21 (dd, Found: C, 54.31; H, 5.11; N, J = 11.62, 2.27 Hz, 1 H) 6.99 (dd, J = 8.84, 14.20. 2.27 Hz, 1 H) 4.09 (s, 3 H) 2.91 (s, 2 H) 2.72 (s, 3 H) 2.72 (s, 3 H) 1.44 (s, 6 H); 133 456.5 C22H24N4O5S ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H) 457.00 (M + H)⁺ 8.08 (s, 1 H) 7.88 (s, 2 H) 7.09 (s, 4 H) 4.13 (s, 3 H) 3.14 (s, 2 H) 2.92 (s, 2 H) 1.49 (s, 6 H) 1.32 (s, 3 H); 134 471.5 C22H25N5O5S ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1 H) 472.00 (M + H)⁺ 8.08 (s, 1 H) 7.73-7.80 (m, 1 H) 7.77 (d, J = 8.84 Hz, 1 H) 7.09 (d, J = 1.01 Hz, 1 H) 7.10 (s, 1 H) 7.08 (s, 1 H) 7.05-7.07 (m, 1 H) 4.12 (s, 3 H) 2.91 (s, 2 H) 2.74 (s, 6 H) 1.51 (s, 6 H); 135 474.5 C22H23FN4O5S ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1 H) 475.00 (M + H)⁺ Calcd. for C₂₂H₂₃FN₄O₅S: C, 8.09 (s, 1 H) 7.86-7.93 (m, 1 H) 55.43; H, 4.91; N, 11.75; 7.06-7.13 (m, 2 H) 6.88 (dd, J = 8.59, 2.27 Hz, 1 Found: C, 55.44; H, 4.93; N, H) 6.80 (dd, J = 10.99, 2.40 Hz, 1 H) 11.80. 4.13 (s, 3 H) 3.32 (q, J = 7.58 Hz, 2 H) 2.91 (s, 2 H) 1.51 (s, 6 H) 1.34 (t, J = 7.45 Hz, 3 H); 136 473.5 C23H24FN3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H) 474.20 (M + H)⁺ Calcd. for C₂₃H₂₄FN₃O₅S: C, 7.89 (t, J = 8.21 Hz, 1 H) 7.30 (s, 1 H) 58.34; H, 5.11; N, 8.87; 7.10 (s, 2 H) 6.84-6.91 (m, 1 H) Found: C, 58.34; H, 5.12; N, 6.74-6.83 (m, 2 H) 3.82 (s, 3 H) 3.32 (q, J = 7.49 Hz, 8.88. 2 H) 2.90 (s, 2 H) 1.51 (s, 6 H) 1.34 (t, J = 7.45 Hz, 3 H); 137 476 C22H22ClN3O5S ¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, 478.00 (M + H)⁺ Calcd. for C₂₂H₂₂ClN₃O₅S•0.35 J = 2.27 Hz, 1 H) 7.86 (dd, J = 8.59, 2.27 Hz, H₂O•0.75 AcOH: C, 1 H) 7.47 (d, J = 2.27 Hz, 1 H) 7.15 (d, 53.53; H, 4.91; N, 7.97; J = 8.84 Hz, 2 H) 7.07 (d, J = 1.26 Hz, 1 H) Found: C, 53.52; H, 4.98; N, 6.55 (d, J = 2.27 Hz, 1 H) 3.80 (s, 3 H) 8.15. 3.15 (s, 3 H) 2.94 (s, 2 H) 1.48 (s, 6 H); 138 507.5 C22H23F2N5O5S ¹H NMR (400 MHz, CD₃OD) δ 7.96 (s, 1 508.00 (M + H)⁺ Calcd. for C₂₂H₂₃F₂N₅O₅S•1.25 H) 7.76 (dd, J = 9.98, 6.19 Hz, 1 H) 7.22 (d, H₂O: C, 49.85; H, 4.85; J = 1.26 Hz, 1 H) 7.16 (s, 1 H) 7.08 (dd, N, 13.21; Found: C, 49.49; J = 10.48, 6.44 Hz, 1 H) 4.11 (s, 3 H) H, 4.47; N, 13.09. 3.04 (s, 2 H) 2.84 (d, J = 1.77 Hz, 6 H) 1.52 (s, 6 H); 139 476 C22H22ClN3O5S ¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, 476.00 (M + H)⁺ J = 8.84 Hz, 1 H) 7.48 (d, J = 2.27 Hz, 1 H) 7.26 (d, J = 2.53 Hz, 1 H) 7.18 (d, J = 10.86 Hz, 2 H) 7.09 (dd, J = 8.84, 2.27 Hz, 1 H) 6.56 (d, J = 2.27 Hz, 1 H) 3.81 (s, 3 H) 3.28 (s, 3 H) 2.91 (s, 2 H) 1.47 (s, 6 H); 140 486.5 C23H23FN4O5S ¹H NMR (400 MHz, CD₃OD) δ 7.94 (s, 1 487.20 (M + H)⁺ Calcd. for C₂₃H₂₃FN₄O₅S•0.24 H) 7.82-7.89 (m, 1 H) 7.19-7.22 (m, 2 H2O: C, 56.28; H, H) 6.93-7.02 (m, 2 H) 4.09 (s, 3 H) 4.82; N, 11.41; Found: C, 2.93 (s, 2 H) 2.83 (ddd, J = 8.84, 4.04, 1.26 Hz, 56.29; H, 4.74; N, 11.31. 1 H) 1.48 (s, 6 H) 1.21-1.31 (m, 2 H) 1.07-1.16 (m, 2 H); 141 485.5 C24H24FN3O5S ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1 H) 486.00 (M + H)⁺ Calcd. for C₂₄H₂₄FN₃O₅S•0.27 7.85 (t, J = 8.34 Hz, 1 H) 7.29 (d, J = 2.27 Hz, H₂O: C, 58.70; H, 5.04; 1 H) 7.08 (s, 2 H) 6.85 (dd, J = 8.84, N, 8.55; Found: C, 58.71; H, 2.27 Hz, 1 H) 6.77-6.82 (m, 2 H) 3.80 (s, 5.19; N, 8.42. 3 H) 2.91 (s, 2 H) 2.74 (dd, J = 12.00, 3.66 Hz, 1 H) 1.51 (s, 6 H) 1.40 (dd, J = 4.67, 2.15 Hz, 2 H) 1.10 (dd, J = 7.71, 1.89 Hz, 2 H);

The appropriate methyl ester intermediates to the above compounds were prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) and the appropriate fluorophenyl sulfones or sulfonamides.

# Structure Name NMR m/z 120a

4-(2-Fluoro-4- methanesulfonyl- phenoxy)-2,2-dimethyl- 6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd, J = 9.60, 2.02 Hz, 1 H) 7.69 (dd, J = 8.46, 1.14 Hz, 1 H) 7.25-7.28 (m, 1 H) 7.16 (s, 1 H) 7.08 (t, J = 8.08 Hz, 1 H) 3.88 (s, 3 H) 3.10 (s, 3 H) 2.97 (s, 2 H) 1.51 (s, 6 H); 395.00 (M + H)⁺ 124a

4-[4-(Azetidine-1- sulfonyl)-phenoxy]-2,2- dimethyl-2,3-dihydro- benzofuran-6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.84 Hz, 2 H) 7.28 (s, 1 H) 7.27 (s, 1 H) 7.09 (d, J = 8.84 Hz, 2 H) 3.89 (s, 3 H) 3.81 (t, J = 7.58 Hz, 4 H) 2.90 (s, 2 H) 2.08-2.17 (m, 2 H) 1.49 (s, 6 H); 418.00 (M + H)⁺ 126a

4-(4-Ethanesulfonyl- phenoxy)-2,2-dimethyl- 2,3-dihydro-benzofuran- 6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.84 Hz, 2 H) 7.27 (s, 1 H) 7.24 (s, 1 H) 7.07 (d, J = 8.84 Hz, 2 H) 3.88 (s, 3 H) 3.13 (q, J = 7.33 Hz, 2 H) 2.88 (s, 2 H) 1.48 (s, 6 H) 1.31 (t, J = 7.45 Hz, 3 H); 391.00 (M + H)⁺ 128a

4-(4-Dimethylsulfamoyl- phenoxy)-2,2-dimethyl- 2,3-dihydro-benzofuran- 6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 8.84 Hz, 2 H) 7.27 (d, 1 H) 7.24 (d, J = 1.26 Hz, 1 H) 7.06 (d, J = 8.84 Hz, 2 H) 3.88 (s, 3 H) 2.89 (s, 2 H) 2.73 (s, 6 H) 1.49 (s, 6 H); 406.00 (M + H)⁺ 129a

4-(4- Cyclopropanesulfonyl- phenoxy)-2,2-dimethyl- 2,3-dihydro-benzofuran- 6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J = 8.84 Hz, 2 H) 7.26-7.28 (m, 1 H) 7.24 (s, 1 H) 7.07 (d, J = 8.84 Hz, 2 H) 3.85-3.91 (m, 3 H) 2.89 (s, 2 H) 2.48 (tt, J = 7.96, 4.80 Hz, 1 H) 1.49 (s, 6 H) 1.35 (dt, J = 6.57, 4.67 Hz, 2 H) 1.02- 1.10 (m, 2 H); 403.00 (M + H)⁺ 130a

4-(4-Dimethylsulfamoyl- 3-fluoro-phenoxy)-2,2- dimethyl-2,3-dihydro- benzofuran-6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.78- 7.84 (m, 1 H) 7.30 (d, J = 1.01 Hz, 1 H) 7.26 (d, J = 1.26 Hz, 1 H) 6.81 (dd, J = 8.72, 2.40 Hz, 1 H) 6.75 (dd, J = 11.12, 2.27 Hz, 1 H) 3.90 (s, 3 H) 2.89 (s, 2 H) 2.85 (s, 3 H) 2.84 (s, 3 H) 1.49 (s, 6 H); 424.00 (M + H)⁺ 135a

4-(4-Ethanesulfonyl-3- fluoro-phenoxy)-2,2- dimethyl-2,3-dihydro- benzofuran-6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.08 Hz, 1 H) 7.31 (d, J = 1.26 Hz, 1 H) 7.27 (d, J = 1.26 Hz, 1 H) 6.85 (dd, J = 8.72, 2.15 Hz, 1 H) 6.77 (dd, J = 11.12, 2.27 Hz, 1 H) 3.90 (s, 3 H) 3.31 (q, J = 7.33 Hz, 2 H) 2.88 (s, 2 H) 1.49 (s, 6 H) 1.27 (t, J = 7.20 Hz, 3 H); 409.00 (M + H)⁺ 138a

4-(4-Dimethylsulfamoyl- 2,5-difluoro-phenoxy)- 2,2-dimethyl-2,3-dihydro- benzofuran-6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.70 (dd, J = 9.73, 6.19 Hz, 1 H) 7.29 (d, J = 1.26 Hz, 1 H) 7.21 (d, J = 1.26 Hz, 1 H) 6.73 (dd, J = 10.11, 6.32 Hz, 1 H) 3.90 (s, 3 H) 2.97 (s, 2 H) 2.82-2.90 (m, 6 H) 1.51 (s, 6 H); 442.00 (M + H)⁺ 140a

4-(4- Cyclopropanesulfonyl-3- fluoro-phenoxy)-2,2- dimethyl-2,3-dihydro- benzofuran-6-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ 7.81- 7.89 (m, 1 H) 7.29-7.33 (m, 1 H) 7.26 (s, 1 H) 6.83 (dd, J = 8.84, 2.27 Hz, 1 H) 6.78 (dd, J = 10.99, 2.40 Hz, 1 H) 3.90 (s, 3 H) 2.89 (s, 2 H) 2.73 (d, J = 1.26 Hz, 1 H) 1.50 (s, 6 H) 1.34-1.43 (m, 2 H) 1.04-1.13 (m, 2 H); 421.00 (M + H)⁺

Example 142 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1 from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (142a) (80 mg, 0.21 mmol) to give a white solid (91 mg, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1 H) 8.06 (s, 1 H) 7.35 (t, J=8.08 Hz, 1 H) 7.08 (s, 2 H) 6.77 (dd, J=8.34, 2.27 Hz, 1 H) 6.66 (dd, J=10.61, 2.27 Hz, 1 H) 4.08 (s, 3 H) 3.11 (s, 3 H) 2.97 (s, 3 H) 2.89 (s, 2 H) 1.48 (s, 6 H); LCMS for C₂₃H₂₄FN₅O₄ m/z 454.20 (M+H⁺); Anal. Calcd. for C₂₃H₂₄FN₅O₄.0.47 H₂O: C, 59.80; H, 5.44; N, 15.16; Found: C, 59.77; H, 5.21; N, 15.06.

Preparation of Intermediate 142a 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-N,N-dimethyl-benzamide (589 mg, 2.65 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (652 mg, 2.65 mmol) to give a white solid (861 mg, 84% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.43 (m, 1 H) 7.25 (s, 1 H) 7.22 (s, 1 H) 6.75-6.84 (m, 1 H) 6.66-6.73 (m, 1 H) 3.88 (s, 3 H) 3.13 (s, 3 H) 2.98 (s, 3 H) 2.90 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₁H₂₂FNO₅ m/z 388.00 (M+H)⁺.

Example 143 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-isoxazol-3-yl)-amide

To a solution of 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (66 mg, 0.177 mmol) in 3 mL of CH₂Cl₂ was added thionyl chloride (0.0154 mL, 0.212 mmol), followed by 3 drops of DMF. The mixture was refluxed for 1.5 h, then concentrated and dried under vacuum. The residue was dissolved in 3 mL of CH₂Cl₂, added 3-amino-5-methylisoxazole (22.6 mg, 0.230 mmol) at 0° C., followed by DMAP (52 mg, 0.354 mmol). The mixture was stirred at 0° C. to room temperature for 1 hr and heated at 40° C. overnight, then concentrated and purified by flash column chromatography with 40-55% EtOAc in hexanes to give a white solid (8 mg, 10% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.06 (s, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.11 (d, J=1.77 Hz, 2 H) 6.76-6.84 (m, 2 H) 6.70 (dd, J=10.61, 2.27 Hz, 1 H) 3.13 (s, 3 H) 2.98 (br. s., 3 H) 2.91 (s, 2 H) 2.42 (s, 3 H) 1.50 (s, 6 H); LCMS for C₂₄H₂₄FN₃O₅ m/z 454.00 (M+H⁺).

Preparation of Intermediate 143a 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid

The title compound was prepared in a similar manner as described for Intermediate 15a, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (142a). ¹H NMR (400 MHz, CDCl₃)) δ 7.40 (t, J=7.96 Hz, 1 H) 7.27-7.33 (m, 2 H) 6.80 (dd, J=8.34, 2.02 Hz, 1 H) 6.70 (dd, J=10.61, 2.27 Hz, 1 H) 3.10-3.18 (m, 3 H) 3.00 (br. s., 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₀H₂₀FNO₅ m/z 374.00 (M+H).

Example 144 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid isoxazol-3-ylamide

To a solution of 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (80 mg, 0.21 mmol), 3-aminoisoxazole (36 mg, 0.429 mmol) and triethylamine (0.0597 mL, 0.4294 mmol) in 2 mL of DMF was added HATU (163 mg, 0.429 mmol). The mixture was stirred at 50° C. overnight, and purified by reverse phase column chromatography to give a white solid (3.3 mg, 4% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1 H) 7.39 (t, J=8.08 Hz, 1 H) 7.27 (s, 1 H) 7.20 (d, J=1.77 Hz, 1 H) 7.13 (d, J=4.55 Hz, 2 H) 6.82 (dd, J=8.59, 2.27 Hz, 1 H) 6.71 (dd, J=10.61, 2.27 Hz, 1 H) 3.16 (s, 3 H) 3.00 (s, 3 H) 2.92 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₃H₂₂FN₃O₅ m/z 440.20 (M+H⁺).

Example 145 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-hydroxymethyl-pyridin-2-yl)-amide

To a solution of 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (381 mg, 1.02 mmol), 5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (22a) (365 mg, 1.53 mmol) and triethylamine (0.284 mL, 2.04 mmol) in 5 mL of DMF was added HATU (776 mg, 2.04 mmol). The mixture was stirred at 50° C. overnight, quenched with water, extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried with Na₂SO₄, concentrated and the resulting oil was purified by Biotage column chromatography with 50-100% EtOAc in hexanes to give a yellow solid (120 mg, 25% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.76 (br. s., 1 H) 8.29 (d, J=8.59 Hz, 1 H) 8.21 (d, J=1.77 Hz, 1 H) 7.74 (dd, J=8.59, 2.27 Hz, 1 H) 7.35 (t, J=8.08 Hz, 1 H) 7.27 (s, 1 H) 7.11 (d, J=5.81 Hz, 1 H) 6.78 (dd, J=8.46, 2.40 Hz, 1 H) 6.68 (dd, J=10.61, 2.27 Hz, 1 H) 4.66 (s, 2 H) 3.11 (s, 3 H) 2.96 (s, 3 H) 2.88 (s, 2 H) 1.48 (s, 6 H); LCMS for C₂₆H₂₆FN₃O₅ m/z 480.20 (M+H).

Example 146 6-{[4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbonyl]-amino}-nicotinamide

The title compound was prepared in a similar manner as described for Example 144, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (80 mg, 0.21 mmol) and 6-aminonicotinamide (58.8 mg, 0.429 mmol) to give a brown solid (5 mg, 5% yield). ¹H NMR (400 MHz, MeOD.) δ 8.82 (d, J=1.52 Hz, 1 H) 8.14-8.32 (m, 2 H) 7.31-7.44 (m, 1 H) 7.18 (dd, J=8.34, 1.26 Hz, 2 H) 6.80-6.97 (m, 2 H) 3.10 (s, 3 H) 2.98 (s, 3 H) 2.93 (s, 2 H) 1.47 (s, 6 H); LCMS for C₂₆H₂₅FN₄O₅ m/z 493.20 (M+H⁺).

Example 147 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-cyclopropylaminomethyl-pyridin-2-yl)-amide

To a solution of 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-formyl-pyridin-2-yl)-amide (147a) (88 mg, 0.18 mmol) in 3 mL of MeOH was added aminocyclopropane (31.6 mg, 0.553 mmol). The mixture was heated at 40° C. for 1 hr, then NaCNBH₃ (29 mg, 0.461 mmol) was added. The reaction mixture was heated at 40° C. for 1 hr, and quenched with 14 drops of AcOH, concentrated and purified by reverse phase column chromatography to give a white solid (26 mg, 27% yield). ¹H NMR (400 MHz, MeOD.) δ 8.38 (d, J=2.02 Hz, 1 H) 8.21 (d, J=8.59 Hz, 1 H) 7.88 (dd, J=8.59, 2.27 Hz, 1 H) 7.40 (t, J=8.08 Hz, 1 H) 7.10-7.24 (m, 2 H) 6.80-6.98 (m, 2 H) 4.08 (s, 2 H) 3.11 (s, 3 H) 2.99 (s, 3 H) 2.94 (s, 2 H) 2.38-2.51 (m, 1 H) 1.48 (s, 6 H) 0.67-0.74 (m, 2 H) 0.58-0.65 (m, 2 H); LCMS for C₂₉H₃₁FN₄O₄ m/z 519.20 (M+H⁺); Anal. Calcd. for C₂₉H₃₁FN₄O₄.0.35 TFA.0.9 H₂O: C, 62.07; H, 5.81; N, 9.75; Found: C, 61.98; H, 5.95; N, 10.05.

Preparation of Intermediate 147a 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-formyl-pyridin-2-yl)-amide

To a solution of 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-hydroxymethyl-pyridin-2-yl)-amide (145) (88 mg, 0.18 mmol) in 3 mL CH₂Cl₂ was added Dess-Martin periodinane (93.4 mg, 0.22 mmol) at 0° C. The mixture was stirred at 0° C. for 1.5 hr. The reaction was quenched with water, extracted with 3×CHCl₃. The combined organic layer was dried with Na₂SO₄ and concentrated. The resulting oil was taken into the next step without further purification. LCMS for C₂₆H₂₄FN₃O₅ m/z 478.20 (M+H⁺).

Example 148 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 144, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (60 mg, 0.16 mmol) and 2-amino-5-methylpyridine (34.8 mg, 0.321 mmol) to give a brown solid (25 mg, 34% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.98 (br. s., 1 H) 8.19 (d, J=8.34 Hz, 1 H) 8.11 (s, 1 H) 7.66 (dd, J=8.46, 1.89 Hz, 1 H) 7.31-7.43 (m, 1 H) 7.12 (s, 1 H) 7.07 (d, J=1.26 Hz, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.69 (dd, J=10.61, 2.27 Hz, 1 H) 3.14 (s, 3 H) 2.98 (s, 3 H) 2.91 (s, 2 H) 2.35 (s, 3 H) 1.50 (s, 6 H); LCMS for C₂₆H₂₆FN₃O₄ m/z 464.20 (M+H⁺); Anal. Calcd. for C₂₆H₂₆FN₃O₄.0.27 TFA.1.0 H₂O: C, 62.22; H, 5.56; N, 8.20; Found: C, 61.87; H, 5.36; N, 8.56.

Example 149 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 4-(4-dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (149c) (130 mg, 0.366 mmol), 3-amino-1-methyl-pyrazole (71.1 mg, 0.732 mmol) and triethylamine (0.102 ml, 0.732 mmol) in 3 mL of DMF was added HATU (278 mg, 0.732 mmol). The mixture was stirred at 50° C. for 2 hr, quenched with water, extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried with Na₂SO₄, concentrated and purified by Biotage column chromatography with 75-100% EtOAc in hexanes to give a white solid (134 mg, 84% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 1 H) 7.38-7.46 (m, 2 H) 7.24-7.28 (m, 1 H) 7.01 (d, J=2.78 Hz, 2 H) 6.97 (d, J=8.59 Hz, 2 H) 6.77 (d, J=2.02 Hz, 1 H) 3.76 (d, 3 H) 3.07 (d, J=22.48 Hz, 6 H) 2.89 (s, 2 H) 1.47 (s, 6 H); LCMS for C₂₄H₂₆N₄O₄ m/z 435.20 (M+H⁺); Anal. Calcd. for C₂₄H₂₆N₄O₄.0.7 H₂O: C, 64.47; H, 6.18; N, 12.53; Found: C, 64.22; H, 6.11; N, 12.54.

Preparation of Intermediate 149a 4-Bromo-N,N-dimethyl-benzamide

To a solution of 4-bromobenzoyl chloride (2.00 g, 9.11 mmol) and dimethyl amine hydrochloride (892 mg, 10.90 mmol) in 20 mL of CH₂Cl₂ was added triethylamine (3.81 mL, 27.30 mmol). The mixture was stirred at room temperature for 2 h, quenched with water, extracted with 3×CHCl₃, dried with Na₂SO₄, concentrated and purified by Biotage column chromatography with 1-4% MeOH in 1:1 EtOAc/CH₂Cl₂ to give a white solid (1.73 g, 83% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.65 (m, 2 H) 7.20-7.37 (m, 2 H) 3.05 (d, J=50.78 Hz, 6 H); LCMS for C₉H₁₀BrNO m/z 228.00 and 230.00 (M+H)⁺

Preparation of Intermediate 149b 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

A mixture of 4-bromo-N,N-dimethyl-benzamide (149a) (428 mg, 1.87 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (500 mg, 2.25 mmol), K₃PO₄ (796 mg, 3.75 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (21 mg, 0.094 mmol), and Pd(OAc)₂ (39.8 mg, 0.094 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 5 hr, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 20-55% EtOAc in hexanes to give a yellow foam (662 mg, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.50 (m, 2 H) 7.20 (dd, J=10.36, 1.26 Hz, 2 H) 6.92-7.04 (m, 2 H) 3.86 (s, 3 H) 3.07 (br. s., 6 H) 2.90 (s, 2 H) 1.48 (s, 6 H); LCMS for C₂₁H₂₃NO₅ m/z 370.20 (M+H⁺).

Preparation of Intermediate 149c 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid

To a solution of 4-(4-dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (149b) (662 mg, 1.79 mmol) in 10 mL MeOH was added 1N aqueous NaOH (3.58 mL, 3.58 mmol). The mixture was stirred at room temperature overnight, then acidified to pH ˜1 with 1N aqueous HCl, extracted with 3×EtOAc, dried over Na₂SO₄, concentrated to give a white solid (624 mg, 98% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J=8.59 Hz, 2 H) 7.25 (dd, J=8.08, 1.26 Hz, 2 H) 6.92-7.02 (m, 2 H) 3.08 (br. s., 6 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₀H₂₁NO₅ m/z 356.20 (M+H⁺).

Examples 150-158 were prepared in a similar manner as described for Example 144 from 4-(4-dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (149c) and the appropriate amino heterocycles.

Example 155 was prepared from 4-(4-dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (149c) and 5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (22a).

Example 150 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

Example 151 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid pyrazin-2-ylamide

Example 152 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1H-pyrazol-3-yl)-amide

Example 153 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

Example 154 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-isoxazol-3-yl)-amide

Example 155 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-hydroxymethyl-pyridin-2-yl)-amide

Example 156 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid pyrimidin-4-ylamide

Example 157 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid pyridin-2-ylamide

Example 158 4-(4-Dimethylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid isoxazol-3-ylamide

Example MW MF NMR m/z Elemental Analysis 150 445.5 C26H27N3O4 ¹H NMR (400 MHz, CDCl₃)) δ 8.99 (br. s., 446.00 (M + H⁺) Calcd. for C₂₆H₂₇N₃O₄•0.3 1 H) 8.20 (d, J = 8.59 Hz, 1 H) 8.10 (d, TFA•0.4 H₂O: C, 65.61; H, J = 2.02 Hz, 1 H) 7.64 (dd, J = 8.59, 2.02 Hz, 5.82; N, 8.63; Found: C, 1 H) 7.34-7.47 (m, 2 H) 6.92-7.13 (m, 4 65.22; H, 5.79; N, 8.93. H) 3.05 (br. s., 6 H) 2.92 (s, 2 H) 2.33 (s, 3 H) 1.49 (s, 6 H); 151 432.5 C24H24N4O4 ¹H NMR (400 MHz, CDCl₃)) δ 9.60 (s, 1 H) 433.20 (M + H)⁺ 8.63 (br. s., 1 H) 8.27-8.41 (m, 2 H) 7.37-7.53 (m, 2 H) 6.92-7.12 (m, 4 H) 3.06 (br. s., 6 H) 2.95 (s, 2 H) 1.49 (s, 6 H); 152 420.5 C23H24N4O4 ¹H NMR (400 MHz, CDCl₃)) δ 7.99 (d, 421.20 (M + H⁺) J = 2.78 Hz, 1 H) 7.45 (d, J = 8.59 Hz, 2 H) 7.27 (s, 1 H) 7.12 (s, 1 H) 7.02-7.07 (m, 3 H) 6.03 (d, J = 3.03 Hz, 1 H) 3.08 (br. s., 6 H) 2.96 (s, 2 H) 1.48-1.53 (m, 6 H); 153 435.5 C23H25N5O4 ¹H NMR (400 MHz, CDCl₃)) δ 8.54 (s, 1 H) 436.00 (M + H⁺) Calcd. for C₂₃H₂₅N₅O₄•0.9 8.09 (s, 1 H) 7.44 (d, J = 8.59 Hz, 2 H) TFA: C, 55.36; H, 4.85; N, 7.03 (t, J = 7.71 Hz, 4 H) 4.11 (s, 3 H) 3.10 (br. 13.01; Found: C, 55.05; H, s., 6 H) 2.92 (s, 2 H) 1.50 (s, 6 H); 5.11; N, 13.15. 154 435.5 C24H25N3O5 ¹H NMR (400 MHz, CDCl₃)) δ 9.06 (br. s., 436.00 (M + H⁺) Calcd. for C₂₄H₂₅N₃O₅•0.3 1 H) 7.44 (d, J = 8.34 Hz, 2 H) TFA•0.4 H₂O: C, 61.96; H, 7.04-7.12 (m, 2 H) 7.00 (d, J = 8.59 Hz, 2 H) 5.52; N, 8.81; Found: C, 6.81 (s, 1 H) 3.06 (br. s., 6 H) 2.91 (s, 2 H) 2.41 (s, 61.82; H, 5.62; N, 9.02. 3 H) 1.49 (s, 6 H);  155* 461.5 C26H27N3O5 ¹H NMR (400 MHz, CDCl₃)) δ 9.03 (br. s., 462.00 (M + H)⁺ 1 H) 8.15-8.37 (m, 2 H) 7.84 (dd, J = 8.46, 1.89 Hz, 1 H) 7.36-7.47 (m, 2 H) 6.94-7.14 (m, 4 H) 4.71 (s, 2 H) 3.11 (br. s., 6 H) 2.94 (s, 2 H) 1.50 (s, 6 H); 156 432.5 C24H24N4O4 ¹H NMR (400 MHz, CDCl₃)) δ 8.87 (s, 1 H) 433.00 (M + H)⁺ Calcd. for C₂₄H₂₄N₄O₄•0.1 8.57-8.71 (m, 2 H) 8.29 (dd, J = 5.81, 1.26 Hz, TFA•0.4 H₂O: C, 64.44; H, 1 H) 7.39-7.49 (m, 2 H) 5.56; N, 12.42; Found: C, 6.89-7.11 (m, 4 H) 3.05 (br. s., 6 H) 2.93 (s, 2 H) 64.33; H, 5.48; N, 12.46. 1.50 (s, 6 H); 157 431.5 C25H25N3O4 ¹H NMR (400 MHz, CDCl₃)) δ 9.02 (br. s., 432.20 (M + H)⁺ Calcd. for C₂₅H₂₅N₃O₄•0.33 1 H) 8.22-8.41 (m, 2 H) 7.73-7.87 (m, 1 TFA•0.4 H₂O: C, 64.70; H, H) 7.37-7.48 (m, 2 H) 6.93-7.14 (m, 5 5.53; N, 8.82; Found: C, H) 3.05 (br. s., 6 H) 2.92 (s, 2 H) 1.47 (s, 6 64.74; H, 5.57; N, 8.89. H); 158 421.5 C23H23N3O5 ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1 H) 422.00 (M + H⁺) 8.32 (d, J = 1.26 Hz, 1 H) 7.41-7.48 (m, 2 H) 7.27 (s, 1 H) 7.17 (d, J = 1.77 Hz, 1 H) 6.96-7.06 (m, 3 H) 3.06 (br. s., 6 H) 2.92 (s, 2 H) 1.50 (s, 6 H);

Example 159 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (159a) (92 mg, 0.23 mmol) to give a white solid (60 mg, 56% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1 H) 8.08 (s, 1 H) 7.43-7.59 (m, 1 H) 7.07 (s, 2 H) 6.78 (d, J=8.59 Hz, 1 H) 6.67 (dd, J=10.99, 2.40 Hz, 1 H) 4.11-4.25 (m, 4 H) 4.10 (s, 3 H) 2.89 (s, 2 H) 2.34 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₄H₂₄FN₅O₄ m/z 466.20 (M+H⁺); Anal. Calcd. for C₂₄H₂₄FN₅O₄.0.2 CHCl₃: C, 59.35; H, 4.98; N, 14.31; Found: C, 59.68; H, 5.19; N, 14.08.

Preparation of Intermediate 159a 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) and azetidin-1-yl-(4-bromo-2-fluoro-phenyl)-methanone. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (t, J=8.21 Hz, 1 H) 7.25 (s, 1 H) 7.22 (s, 1 H) 6.78 (dd, J=8.59, 2.27 Hz, 1 H) 6.66 (dd, J=11.12, 2.27 Hz, 1 H) 4.18-4.29 (m, 2 H) 4.15 (t, J=7.58 Hz, 2 H) 3.88 (s, 3 H) 2.88 (s, 2 H) 2.30-2.41 (m, J=7.75, 7.75, 7.75, 7.58 Hz, 2 H) 1.48 (s, 6 H); LCMS for C₂₂H₂₂FNO₅ m/z 400.20 (M+H)⁺.

Example 160 4-[4-(Azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-[4-(azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (35b) (94 mg, 0.250 mmol) to give a white solid (66 mg, 60% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1 H) 8.01-8.15 (m, 1 H) 7.64 (t, J=8.21 Hz, 2 H) 7.02-7.05 (m, 2 H) 6.99 (d, J=8.59 Hz, 2 H) 4.25-4.35 (m, 4 H) 4.11 (s, 3 H) 2.90 (s, 2 H) 2.37 (t, J=7.71 Hz, 2 H) 1.49 (s, 6 H); LCMS for C₂₄H₂₅N₅O₄ m/z 448.20 (M+H⁺); Anal. Calcd. for C₂₄H₂₅N₅O₄.0.3 H₂O: C, 63.65; H, 5.70; N, 15.46; Found: C, 63.90; H, 5.58; N, 15.40.

Example 161 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid dimethylamide

The title compound was prepared in a similar manner as described for Example 1 from 4-(6-dimethylcarbamoyl-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (161b) (111 mg, 0.30 mmol) to give a white solid (87 mg, 67% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1 H) 8.30 (d, J=2.27 Hz, 1 H) 7.67 (d, J=8.59 Hz, 1 H) 7.18-7.33 (m, 2 H) 7.03 (s, 2 H) 6.76 (d, J=2.27 Hz, 1 H) 3.72 (s, 3 H) 3.13 (d, J=7.33 Hz, 6 H) 2.89 (s, 2 H) 1.47 (s, 6 H); LCMS for C₂₃H₂₅N₅O₄ m/z 436.30 (M+H⁺); Anal. Calcd. for C₂₃H₂₅N₅O₄.0.22 H₂O: C, 62.86; H, 5.84; N, 15.94; Found: C, 62.90; H, 5.89; N, 16.01.

Preparation of Intermediate 161a 5-Bromo-pyridine-2-carboxylic acid dimethylamide

To a solution of 5-bromopyridine-2-caboxylic acid (3.00 g, 14.85 mmol), dimethyl amine hydrochloride (1.82 g, 22.30 mmol) and triethylamine (6.21 ml, 44.60 mmol) in 20 mL of DMF was added HATU (8.47 g, 22.30 mmol). The mixture was stirred at room temperature overnight, quenched with water, extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried with Na₂SO₄, concentrated and purified by Biotage column chromatography with 60-70% EtOAc in hexanes to give a yellow oil (1.56 g, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=1.77 Hz, 1 H) 7.88 (dd, J=8.34, 2.27 Hz, 1 H) 7.52 (d, J=8.34 Hz, 1 H) 3.06 (d, J=14.15 Hz, 6 H); LCMS for C₈H₉BrN₂O m/z 229.00 (M+H⁺).

Preparation of Intermediate 161b 4-(6-Dimethylcarbamoyl-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

A mixture of 5-bromo-pyridine-2-carboxylic acid dimethylamide (161a) (1.14 g, 4.95 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (1.10 g, 4.95 mmol), and K₃PO₄ (2.10 g, 9.91 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (210 mg, 0.495 mmol), and Pd(OAc)₂ (111 mg, 0.495 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 6 hr, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 35-70% EtOAc in hexanes to give a white foam (238 mg, 13% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=2.78 Hz, 1 H) 7.70 (d, J=8.59 Hz, 1 H) 7.31 (dd, J=8.72, 2.91 Hz, 1 H) 7.25 (d, J=1.26 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 3.87 (s, 3 H) 3.15 (d, J=4.29 Hz, 6 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₀H₂₂N₂O₅ m/z 371.20 (M+H⁺).

Example 162 6-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-N,N-dimethyl-nicotinamide

The title compound was prepared in a similar manner as described for Example 1, from 4-(5-dimethylcarbamoyl-pyridin-2-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (162b) (100 mg, 0.27 mmol), to give a white solid (67 mg, 57% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1 H) 8.28 (d, J=1.77 Hz, 1 H) 7.85 (dd, J=8.46, 2.40 Hz, 1 H) 7.27 (s, 1 H) 7.11 (d, 1 H) 7.14 (dd, J=24.51, 1.26 Hz, 1 H) 6.99 (d, J=9.09 Hz, 1 H) 6.80 (d, J=2.27 Hz, 1 H) 3.80 (s, 3 H) 3.10 (d, J=17.94 Hz, 6 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C₂₃H₂₅N₅O₄ m/z 436.30 (M+H⁺); Anal. Calcd. for C₂₃H₂₅N₅O₄.0.33 H₂O: C, 62.56; H, 5.86; N, 15.87; Found: C, 62.57; H, 5.93; N, 15.87.

Preparation of Intermediate 162a 6-Bromo-N,N-dimethyl-nicotinamide

The title compound was prepared in a similar manner as described for Intermediate 161a, from 6-bromo-nicotinic acid (1.00 g, 4.95 mmol) to give a colorless oil (780 mg, 69% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=2.53 Hz, 1 H) 7.61-7.71 (m, 1 H) 7.56 (d, J=8.08 Hz, 1 H) 3.08 (d, J=41.68 Hz, 6 H); LCMS for C₈H₉BrN₂O m/z 229.00 (M+H)⁺.

Preparation of Intermediate 162b 4-(5-Dimethylcarbamoyl-pyridin-2-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 161b, from 6-bromo-N,N-dimethyl-nicotinamide (162a) (335 mg, 1.46 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (250 mg, 1.12 mmol) to give a white foam (200 mg, 50% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=2.02 Hz, 1 H) 7.83 (dd, J=8.46, 2.40 Hz, 1 H) 7.34 (d, J=1.01 Hz, 1 H) 7.27 (s, 1 H) 6.97 (d, J=8.34 Hz, 1 H) 3.86 (s, 3 H) 3.08 (d, J=21.47 Hz, 6 H) 2.82 (s, 2 H) 1.46 (s, 6 H); LCMS for C₂₀H₂₂N₂O₅ m/z 371.20 (M+H⁺).

Example 163 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 149, from 5-(6-carboxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid (163b) (111 mg, 0.288 mmol) and 3-amino-1-methyl-pyrazole (56 mg, 0.576 mmol) to give a white solid (112 mg, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.19 (s, 1 H) 8.98 (s, 1 H) 8.30 (d, J=2.53 Hz, 1 H) 8.22 (d, J=8.59 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.24-7.28 (m, 1 H) 7.07 (d, J=3.03 Hz, 2 H) 6.79 (d, J=2.02 Hz, 1 H) 6.83 (d, J=2.27 Hz, 1 H) 3.84 (s, 3 H) 3.74 (s, 3 H) 2.89 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₅H₂₅N₇O₄ m/z 488.20 (M+H⁺); Anal. Calcd. for C₂₅H₂₅N₇O₄.0.1 CHCl₃: C, 59.50; H, 5.15; N, 19.35; Found: C, 59.77; H, 5.17; N, 18.96.

Preparation of Intermediate 163a 5-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester

A mixture of t-butyl 5-bromopicolinate (581 mg, 2.25 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (500 mg, 2.25 mmol), K₃PO₄ (956 mg, 4.50 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (96 mg, 0.225 mmol), and Pd(OAc)₂ (51 mg, 0.225 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 3 h, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 15-30% EtOAc in hexanes to give 26 mg of 5-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester and 400 mg mixture of the title compound with ˜40% of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester as a yellow foam. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=2.53 Hz, 1 H) 8.05 (d, J=8.84 Hz, 1 H) 7.23-7.36 (m, 2 H) 7.19 (d, J=1.26 Hz, 1 H) 3.87 (s, 3 H) 2.89 (s, 2 H) 1.64 (s, 9 H) 1.48 (s, 6 H); LCMS for C₂₂H₂₅NO₆ m/z 344.00 (M-tBu+H⁺).

Preparation of Intermediate 163b 5-(6-Carboxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid

To a solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (163a) (110 mg, 0.275 mmol) in 2 mL MeOH and 1 mL THF was added 1N aqueous NaOH (0.55 mL, 0.55 mmol). The mixture was stirred at room temperature overnight, heated at 60° C. for 6 hr, then concentrated, acidified to pH ˜3 with 1N aqueous HCl, extracted with 3×EtOAc, dried over Na₂SO₄, and concentrated to give 113 mg white solid. LCMS for C₁₇H₁₅NO₆ m/z 330.00 (M+H⁺).

Example 164 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyrimidine-2-carboxylic acid dimethylamide

The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (152 mg, 1.56 mmol) and 4-(2-dimethylcarbamoyl-pyrimidin-5-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (164b) (58 mg, 0.16 mmol) to give a white solid (64 mg, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1 H) 8.47 (s, 2 H) 7.20-7.34 (m, 1 H) 7.07 (d, J=1.52 Hz, 2 H) 6.76 (d, J=2.02 Hz, 1 H) 3.73 (s, 3 H) 3.14 (s, 3 H) 2.98 (s, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₂H₂₄N₆O₄ m/z 437.00 (M+H⁺); Anal. Calcd. for C₂₂H₂₄N₆O₄.0.15 CHCl₃: C, 58.55; H, 5.36; N, 18.50; Found: C, 58.59; H, 5.45; N, 18.61.

Preparation of Intermediate 164a 5-Bromo-pyrimidine-2-carboxylic acid dimethylamide

The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyrimidine-2-caboxylic acid (1.03 g, 5.074 mmol) to give a yellow oil (308 mg, 26% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 2 H) 3.17 (s, 3 H) 3.00 (s, 3 H); LCMS for C₇H₈BrN₃O m/z 230.00 and 232.00 (M+H⁺).

Preparation of Intermediate 164b 4-(2-Dimethylcarbamoyl-pyrimidin-5-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 161b, from 5-bromo-pyrimidine-2-carboxylic acid dimethylamide (164a) (271 mg, 1.18 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (262 mg, 1.18 mmol) to give a white foam (110 mg, 25% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 2 H) 7.24-7.36 (m, 1 H) 7.20 (s, 1 H) 3.88 (s, 3 H) 3.17 (s, 3 H) 3.00 (s, 3 H) 2.95 (s, 2 H) 1.51 (s, 6 H); LCMS for C₁₉H₂₁N₃O₅ m/z 372.00 (M+H⁺).

Example 165 5-[2,2-Dimethyl-6-(5-methyl-pyridin-2-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid dimethylamide

The title compound was prepared in a similar manner as described for Example 1, from 4-(6-dimethylcarbamoyl-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (161b) (93 mg, 0.25 mmol) to give a white solid (57 mg, 51% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1 H) 8.31 (d, J=2.78 Hz, 1 H) 8.20 (d, J=8.34 Hz, 1 H) 8.02 (d, J=2.27 Hz, 1 H) 7.53 (dd, J=8.46, 2.15 Hz, 1 H) 7.23-7.35 (m, 2 H) 7.08 (dd, J=13.64, 1.26 Hz, 2 H) 3.13 (d, J=8.34 Hz, 6 H) 2.89 (s, 2 H) 2.27 (s, 3 H) 1.48 (s, 6 H); LCMS for C₂₅H₂₆N₄O₄ m/z 447.00 (M+H⁺); Anal. Calcd. for C₂₅H₂₆N₄O₄.0.5 CHCl₃: C, 60.50; H, 5.28; N, 11.07; Found: C, 60.31; H, 5.31; N, 11.00.

Example 166 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid methylamide

The title compound was prepared in a similar manner as described for Example 1, from 2,2-dimethyl-4-(6-methylcarbamoyl-pyridin-3-yloxy)-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (166b) (174 mg, 0.488 mmol) to give a white solid (147 mg, 71% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H) 8.29 (d, J=2.53 Hz, 1 H) 8.20 (d, J=8.59 Hz, 1 H) 8.08 (s, 1 H) 7.86 (br. s., 1 H) 7.37 (dd, J=8.59, 2.78 Hz, 1 H) 7.26 (d, J=2.27 Hz, 1 H) 6.98-7.10 (m, 2 H) 4.12 (s, 3 H) 3.04 (d, J=5.05 Hz, 3 H) 2.92 (s, 2 H) 1.51 (s, 6 H): LCMS for C₂₂H₂₃N₅O₄ m/z 422.20 (M+H⁺); Anal. Calcd. for C₂₂H₂₃N₅O₄.0.15 CHCl₃: C, 60.55; H, 5.31; N, 15.94; Found: C, 60.68; H, 5.45; N, 15.98.

Preparation of Intermediate 166a 5-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid

A solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (163a) (260 mg, 0.65 mmol) in 4 mL CH₂Cl₂ and 2 mL TFA was stirred at room temperature for 2 hr. The mixture was concentrated, dried under vacuum, and taken to the next step as it is.

Preparation of Intermediate 166b 2,2-Dimethyl-4-(6-methylcarbamoyl-pyridin-3-yloxy)-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

To a solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid (166a) (74 mg, 0.22 mmol) 3 mL CH₂Cl₂ was added 2.0 M oxalyl chloride in THF (0.22 mL, 0.44 mmol), followed by 3 drops of DMF. The mixture was stirred at room temperature for 1 hr. Another 2.0 eq of oxalyl chloride was added. The mixture was stirred at room temperature for 30 min, concentrated, and dried under vacuum. The residue was dissolved in 3 mL CH₂Cl₂, and 2 mL 2.0 M methyl amine in THF was introduced. The mixture was stirred at room temperature overnight, concentrated, and purified by Biotage column chromatography with 30-50% EtOAc in hexanes to give a white solid (37 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=2.78 Hz, 1 H) 8.19 (d, J=8.59 Hz, 1 H) 7.88 (d, J=3.79 Hz, 1 H) 7.34 (dd, J=8.72, 2.65 Hz, 1 H) 7.26-7.30 (m, 2 H) 3.88 (s, 3 H) 3.05 (d, J=5.05 Hz, 3 H) 2.90 (s, 2 H) 1.49 (s, 6 H); LCMS for C₁₉H₂₀N₂O₅ m/z 357.00 (M+H⁺).

Example 167 4-[6-(Azetidine-1-carbonyl)-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-[6-(azetidine-1-carbonyl)-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (167b) (68 mg, 0.178 mmol) to give a white solid (37 mg, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1 H) 8.29 (d, J=2.78 Hz, 1 H) 8.10 (d, J=8.59 Hz, 1 H) 7.31 (dd, 1 H) 7.23-7.33 (m, 1 H) 7.03 (s, 1 H) 7.04 (d, J=7.83 Hz, 1 H) 6.78 (d, J=2.27 Hz, 1 H) 4.70 (t, J=7.71 Hz, 2 H) 4.24 (t, J=7.83 Hz, 2 H) 3.76 (s, 3 H) 2.89 (s, 2 H) 2.29-2.41 (m, 2 H) 1.49 (s, 6 H); LCMS for C₂₄H₂₅N₅O₄ m/z 448.20 (M+H⁺); Anal. Calcd. for C₂₄H₂₅N₅O₄.0.2 AcOH: C, 61.32; H, 5.45; N, 15.05; Found: C, 62.35; H, 5.50; N, 14.94.

Preparation of Intermediate 167a Azetidin-1-yl-(5-bromo-pyridin-2-yl)-methanone

The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyridine-2-caboxylic acid (1.50 g, 7.43 mmol) and azetidine hydrochloride (954 mg, 10.2 mmol) to give a yellow solid (1.38 g, 77% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=2.02 Hz, 1 H) 7.93-7.99 (m, 1 H) 7.90 (d, J=2.27 Hz, 1 H) 4.65 (t, J=7.71 Hz, 2 H) 4.20 (dd, J=8.34, 7.33 Hz, 2 H) 2.27-2.36 (m, 2 H); LCMS for C₉H₉BrN₂O m/z 241.00 (M+H)⁺.

Preparation of Intermediate 167b 4-[6-(Azetidine-1-carbonyl)-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 161b, from azetidin-1-yl-(5-bromo-pyridin-2-yl)-methanone (167a) (1.37 g, 5.68 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.26 g, 5.58 mmol) to give a white foam (738 mg, 34% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=2.78 Hz, 1 H) 8.12 (d, J=8.59 Hz, 1 H) 7.31-7.38 (m, 1 H) 7.27 (s, 1 H) 7.21 (s, 1 H) 4.72 (t, J=7.71 Hz, 2 H) 4.27 (t, J=7.71 Hz, 2 H) 3.89 (s, 3 H) 2.92 (s, 2 H) 2.38 (t, J=7.71 Hz, 2 H) 1.50 (s, 6 H); LCMS for C₂₁H₂₂N₂O₅ m/z 383.20 (M+H⁺).

Example 168 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid ethylamide

The title compound was prepared in a similar manner as described for Example 1 from 4-(6-ethylcarbamoyl-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (168a) (28 mg, 0.076 mmol) to give a white solid (22 mg, 65% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1 H) 8.24 (d, J=2.27 Hz, 1 H) 8.17 (d, J=8.59 Hz, 1 H) 7.88 (br. s., 1 H) 7.34 (dd, J=8.59, 2.78 Hz, 1 H) 7.26 (d, J=2.27 Hz, 1 H) 7.05 (d, J=1.26 Hz, 1 H) 6.99 (d, J=1.26 Hz, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 3.73 (s, 3 H) 3.49 (dd, J=7.20, 5.94 Hz, 2 H) 2.89 (s, 2 H) 1.48 (s, 6 H) 1.19-1.30 (m, 3 H); LCMS for C₂₃H₂₅N₅O₄ m/z 436.20 (M+H⁺); Anal. Calcd. for C₂₃H₂₅N₅O₄.0.12 CHCl₃: C, 61.73; H, 5.63; N, 15.57; Found: C, 61.55; H, 5.63; N, 15.12.

Preparation of Intermediate 168a 4-(6-Ethylcarbamoyl-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 166b, from 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid (166a) (74 mg, 0.22 mmol) and ethyl amine (2.0 M in THF, 1 mL) to give a white solid (28 mg, 35% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=2.78 Hz, 1 H) 8.18 (d, J=8.59 Hz, 1 H) 7.82-7.91 (m, 1 H) 7.34 (dd, J=8.59, 2.78 Hz, 1 H) 7.25 (s, 1 H) 7.19 (d, J=1.01 Hz, 1 H) 3.87 (s, 3 H) 3.52 (dd, J=7.33, 6.06 Hz, 2 H) 2.90 (s, 2 H) 1.49 (s, 6 H) 1.22-1.33 (m, 3 H); LCMS for C₂₀H₂₂N₂O₅ m/z 371.00 (M+H⁺).

Example 169 4-[6-(Azetidine-1-carbonyl)-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-[6-(azetidine-1-carbonyl)-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (167b) (68 mg, 0.18 mmol) to give a white solid (46 mg, 69% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1 H) 8.31 (d, J=2.27 Hz, 1 H) 8.08 (s, 1 H) 8.12 (d, J=8.59 Hz, 1 H) 7.33 (dd, J=8.72, 2.91 Hz, 1 H) 7.05 (dd, J=7.33, 1.26 Hz, 2 H) 4.71 (t, J=7.71 Hz, 2 H) 4.26 (t, J=7.83 Hz, 2 H) 4.12 (s, 3 H) 2.91 (s, 2 H) 2.36 (t, J=7.71 Hz, 2 H) 1.51 (s, 6 H); LCMS for C₂₃H₂₄N₆O₄ m/z 449.20 (M+H⁺); Anal. Calcd. for C₂₃H₂₄N₆O₄.0.2 AcOH: C, 61.03; H, 5.43; N, 18.25; Found: C, 61.14; H, 5.54; N, 18.39.

Example 170 5-[2,2-Dimethyl-6-(2-methyl-2H-[1,2,3]triazol-4-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid methylamide

The title compound was prepared in a similar manner as described for Example 1, from 2,2-dimethyl-4-(6-methylcarbamoyl-pyridin-3-yloxy)-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (166b) (104 mg, 0.292 mmol) to give a white solid (60 mg, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1 H) 8.29 (d, J=2.78 Hz, 1 H) 8.19 (d, J=8.84 Hz, 1 H) 8.08 (s, 1 H) 7.87 (d, J=4.55 Hz, 1 H) 7.37 (dd, J=8.59, 2.78 Hz, 1 H) 7.06 (s, 1 H) 7.04 (s, 1 H) 4.11 (s, 3 H) 3.04 (d, J=5.31 Hz, 3 H) 2.91 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₁H₂₂N₆O₄ m/z 423.20 (M+H⁺); Anal. Calcd. for C₂₁H₂₂N₆O₄.0.2 AcOH.0.2 H₂O: C, 58.67; H, 5.34; N, 19.19; Found: C, 58.48; H, 5.25; N, 19.34.

Example 171 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyrimidine-2-carboxylic acid methylamide

The title compound was prepared in a similar manner as described for Example 1, from 2,2-dimethyl-4-(2-methylcarbamoyl-pyrimidin-5-yloxy)-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (171d) (45 mg, 0.16 mmol) to give a white solid (15 mg, 28% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 2 H) 7.89 (br. s., 2 H) 7.38 (s, 1 H) 7.27 (s, 1 H) 7.08-7.19 (m, 2 H) 3.86 (s, 3 H) 3.08 (d, J=4.80 Hz, 3 H) 2.93 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₁H₂₂N₆O₄ m/z 423.00 (M+H⁺).

Preparation of Intermediate 171a 5-Bromo-pyrimidine-2-carboxylic acid tert-butyl ester

A suspension of 5-bromopyrimidine-2-carboxylic acid (690 mg, 3.40 mmol) in 6.8 mL t-BuOH and 1.9 mL pyridine was stirred at room temperature to 50° C. for 1 hr, and cooled to room temperature. 4-Toluenesulfonyl chloride (1.55 g, 8.12 mmol) was added portion wise. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched with saturated aqueous NaHCO₃ slowly, extracted with 3×Et₂O, dried over Na₂SO₄, and concentrated. The residue was purified by Biotage column chromatography with 15-25% EtOAc in hexanes to give a yellow solid (497 mg, 56% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 2 H) 1.64 (s, 9 H).

Preparation of Intermediate 171b 5-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 161b, from 5-bromo-pyrimidine-2-carboxylic acid tert-butyl ester (171a) (497 mg, 1.92 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (426 mg, 1.92 mmol) to give a yellow oil (83 mg, 11% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 2 H) 7.30 (d, J=1.26 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 3.88 (s, 3 H) 2.92 (s, 2 H) 1.68 (s, 9 H) 1.50 (s, 6 H); LCMS for C₂₁H₂₄N₂O₆ m/z 345.00 (M-tBu+H⁺).

Preparation of Intermediate 171c 5-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid

A solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid tert-butyl ester (171b) (83 mg, 0.21 mmol) in 2 mL CH₂Cl₂ and 1 mL TFA was stirred at room temperature for 2 hr. The mixture was concentrated, dried under vacuum, and taken to the next step as it is.

Preparation of Intermediate 171d 2,2-Dimethyl-4-(2-methylcarbamoyl-pyrimidin-5-yloxy)-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 166b, from 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid (171c) (72.3 mg, 0.21 mmol) and methyl amine (2 mL, 2.0 M solution in THF) to give a white solid (45 mg, 60% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 2 H) 7.88 (d, J=3.79 Hz, 1 H) 7.28 (d, J=10.11 Hz, 1 H) 7.19 (s, 1 H) 3.88 (s, 3 H) 3.08 (d, J=5.05 Hz, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C₁₈H₁₉N₃O₅ m/z 358.20 (M+H⁺).

Example 172 4-[2-(Azetidine-1-carbonyl)-pyrimidin-5-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-[2-(azetidine-1-carbonyl)-pyrimidin-5-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (172b) (76 mg, 0.20 mmol) to give a white solid (18 mg, 20% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (br. s., 2 H) 7.22-7.33 (m, 3 H) 7.09-7.19 (m, 2 H) 4.64 (br. s., 2 H) 4.31 (br. s., 2 H) 3.88 (s, 3 H) 2.97 (s, 2 H) 2.29-2.42 (m, 2 H) 1.50 (s, 6 H); LCMS for C₂₃H₂₄N₈O₄ m/z 449.00 (M+H⁺).

Preparation of Intermediate 172a Azetidin-1-yl-(5-bromo-pyrimidin-2-yl)-methanone

The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyrimidine-2-caboxylic acid (1.60 g, 7.877 mmol) and azetidine hydrochloride (1.11 g, 11.8 mmol) to give a yellow solid (331 mg, 17% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 2 H) 4.64 (t, J=7.71 Hz, 2 H) 4.29 (t, J=7.83 Hz, 2 H) 2.29-2.41 (m, 2 H); LCMS for C₈H₈BrN₃O m/z 241.00 and 243.00 (M+H)⁺.

Preparation of Intermediate 172b 4-[2-(Azetidine-1-carbonyl)-pyrimidin-5-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 161b, from azetidin-1-yl-(5-bromo-pyrimidin-2-yl)-methanone (172a) (331 mg, 1.37 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (304 mg, 1.37 mmol) to give a white foam (136 mg, 36% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1 H) 8.53 (s, 2 H) 7.29 (s, 1 H) 4.64 (t, J=7.45 Hz, 2 H) 4.30 (t, J=7.58 Hz, 2 H) 3.88 (s, 3 H) 2.93 (s, 2 H) 2.36 (t, J=7.45 Hz, 2 H) 1.50 (s, 6 H); LCMS for C₂₀H₂₁ N₃O₅ m/z 384.00 (M+H⁺).

Example 173 4-[6-(Azetidine-1-carbonyl)-5-fluoro-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

A mixture of azetidin-1-yl-(3,5-difluoro-pyridin-2-yl)-methanone (173a) (174 mg, 0.877 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (210 mg, 0.731 mmol), and Cs₂CO₃ (476 mg, 1.46 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H₂O, and extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried over Na₂SO₄ and concentrated. The residue was purified by SFC column chromatography to give a white solid (241 mg, 68% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.64 (br. S, 1 H) 8.20 (d, J=1.76 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.21 (s, 1H) 7.18 (d, J=1.01 Hz, 1 H) 7.08 (dd, J=10.83, 2.27 Hz, 1 H) 6.84 (d, J=2.27 Hz, 1 H) 4.38 (t, J=7.68 Hz, 2 H) 4.25 (t, J=7.81 Hz, 2 H) 3.80 (s, 3 H) 2.97 (s, 2 H) 2.24-2.43 (m, 2 H) 1.50 (s, 6 H); LCMS for C₂₄H₂₄FN₈O₄ m/z 466.20 (M+H)⁺; Anal. Calcd. for C₂₄H₂₄FN₈O₄.0.40 AcOH: C, 60.85; H, 5.27; N, 14.31; Found: C, 60.87; H, 5.23; N, 14.42.

Preparation of Intermediate 173a Azetidin-1-yl-(3,5-difluoro-pyridin-2-yl)-methanone

The title compound was prepared in a similar manner as described for Intermediate 161a, from 3,4-difluoropyridine-2-caboxylic acid (1.00 g, 6.29 mmol) and azetidine hydrochloride (882 mg, 9.43 mmol) to give a white solid (630 mg, 51% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.51 (m, 1 H) 7.66 (dd, J=9.09, 1.77 Hz, 1 H) 4.26 (d, J=7.58 Hz, 2 H) 4.18 (t, J=7.83 Hz, 2 H) 2.29 (dt, J=15.66, 7.83 Hz, 2 H); LCMS for C₉H₈F₂N₂O m/z 199.00 (M+H)⁺.

Example 174 5-[2,2-Dimethyl-6-(2-methyl-2H-[1,2,3]triazol-4-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid ethylamide

The title compound was prepared in a similar manner as described for Example 1, from 4-(6-ethylcarbamoyl-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (168a) to give a white solid (287 mg, 36% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.46 (br. s., 1 H) 8.29 (d, J=2.02 Hz, 1 H) 8.19 (d, J=8.59 Hz, 1 H) 8.08 (s, 1 H) 7.86 (br. s., 1 H) 7.36 (dd, J=8.59, 2.78 Hz, 1 H) 7.28 (s, 1 H) 7.04 (d, J=1.26 Hz, 1 H) 4.11 (s, 3 H) 3.51 (d, J=6.06 Hz, 2 H) 2.91 (s, 2 H) 1.51 (s, 6 H) 1.28 (t, J=7.33 Hz, 3 H); LCMS for C₂₂H₂₄N₆O₄ m/z 437.00 (M+H⁺); Anal. Calcd. for C₂₂H₂₄N₆O₄.0.2 AcOH: C, 59.99; H, 5.57; N, 18.97; Found: C, 59.84; H, 5.47; N, 18.97.

Example 175 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-ethylamino-pyridine-2-carboxylic acid ethylamide

The title compound was prepared in a similar manner as described for Example 1, from ethyl amine hydrochloride (278 mg, 3.41 mmol) and 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester (175b) (150 mg, 0.341 mmol) to give a white solid (111 mg, 68% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.36-8.50 (m, 2 H) 7.91 (t, J=5.56 Hz, 1 H) 7.47 (d, J=2.27 Hz, 1 H) 7.27 (s, 1H) 7.04 (s, 1 H) 7.00 (d, J=1.26 Hz, 1 H) 6.78 (d, J=2.27 Hz, 1 H) 6.50 (d, J=2.27 Hz, 1 H) 3.79 (s, 3 H) 3.33-3.51 (m, 2 H) 3.01-3.15 (m, 2 H) 2.94 (s, 2 H) 1.50 (s, 6 H) 1.19-1.34 (m, 6 H); LCMS for C₂₅H₃₀N₆O₄ m/z 479.20 (M+H⁺); Anal. Calcd. for C₂₅H₃₀N₆O₄: C, 62.75; H, 6.32; N, 17.56; Found: C, 62.63; H, 6.37; N, 17.35.

Preparation of Intermediate 175a 3,5-Difluoro-pyridine-2-carboxylic acid methyl ester

3,5-Difluoropicolinic acid (1.40 g, 8.78 mmol) was dissolved in 30 mL MeOH and 0.5 mL 4.0 M HCl in 1,4-dioxane. The mixture was heated at 60° C. for 1.5 h and concentrated. Saturated aqueous NaHCO₃ was added. The mixture was extracted with EtOAc, dried over Na₂SO₄, and concentrated to give a yellow solid (1.30 g, 86% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=2.27 Hz, 1 H) 7.28-7.47 (m, 1 H) 4.03 (s, 3 H); LCMS for C₇H₅F₂NO₂ m/z 174.00 (M+H⁺).

Preparation of Intermediate 175b 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester

A mixture of 3,5-difluoro-pyridine-2-carboxylic acid methyl ester (175a) (422 mg, 2.44 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (700 mg, 2.44 mmol), and Cs₂CO₃ (1.59 g, 4.88 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H₂O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried over Na₂SO₄ and concentrated. The residue was purified by Biotage column chromatography with 40-70% EtOAc in hexanes to give a white solid (607 mg, 57% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.12 (br. s., 1 H) 8.31 (d, J=2.02 Hz, 1 H) 7.27 (d, J=2.27 Hz, 1 H) 7.12 (d, J=5.81 Hz, 2 H) 6.97-7.07 (m, 1 H) 6.78 (d, J=1.77 Hz, 1 H) 4.00 (s, 3 H) 3.73 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₂H₂₁FN₄O₅ m/z 441.20 (M+H)⁺.

Example 176 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methylamide

To a solution of 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid (176a) (97 mg, 0.23 mmol) in 3 mL CH₂Cl₂ was added 2.0 M oxalyl chloride in THF (0.23 mL, 0.46 mmol), followed by 3 drops of DMF. The mixture was stirred at room temperature for 1 hr, concentrated, and dried under vacuum. The residue was dissolved in 3 mL CH₂Cl₂, and 1 mL 2.0 M methyl amine in THF was added at 0° C., followed by Et₃N (0.091 mL, 0.46 mmol). The mixture was stirred at 0° C. for 1.5 hr. The reaction was quenched with H₂O, extracted with 3×CHCl₃, concentrated, and purified by reverse phase column chromatography to give a white solid (48 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1 H) 8.14 (d, J=2.02 Hz, 1 H) 7.63 (br. s., 1 H) 7.25-7.33 (m, 1 H) 7.03-7.12 (m, 3 H) 6.79 (d, J=1.77 Hz, 1 H) 3.81 (s, 3 H) 2.98-3.06 (m, 3 H) 2.91 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₂H₂₂FN₅O₄ m/z 440.20 (M+H⁺); Anal. Calcd. for C₂₂H₂₂FN₅O₄.0.25 AcOH: C, 59.47; H, 5.10; N, 15.41; Found: C, 59.41; H, 5.04; N, 15.52.

Preparation of Intermediate 176a 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid

To a solution of 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester (175b) (949 mg, 2.15 mmol) in 12 mL THF was added 4 mL of 1.0 N aqueous NaOH. The mixture was heated at 60° C. for 1 hr, and concentrated in vacuo. The residue was acidified to pH ˜1 with 1N aqueous HCl, filtered, washed with water, and dried under vacuum at 60° C. overnight to give an off-white solid (800 mg, 87% yield). LCMS for C₂₁H₁₉FN₄O₅ m/z 427.20 (M+H⁺).

Example 177 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid ethylamide

The title compound was prepared in a similar manner as described for Example 176, from 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid (176a) and ethyl amine (1.0 mL, 2.0 M solution in THF) to give a white solid (203 mg, 64% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1 H) 8.12 (d, J=2.02 Hz, 1 H) 7.65 (t, J=5.43 Hz, 1 H) 7.23-7.32 (m, 1 H) 6.96-7.12 (m, 3 H) 6.78 (d, J=2.02 Hz, 1 H) 3.77 (s, 3 H) 3.40-3.58 (m, 2 H) 2.89 (s, 2 H) 1.50 (s, 6 H) 1.26 (t, J=7.20 Hz, 3 H); LCMS for C₂₃H₂₄FN₅O₄ m/z 454.20 (M+H⁺); Anal. Calcd. for C₂₃H₂₄FN₅O₄.0.10 AcOH: C, 60.65; H, 5.35; N, 15.24; Found: C, 60.62; H, 5.36; N, 15.28.

Example 178 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid dimethylamide

The title compound was prepared in a similar manner as described for Example 1, from dimethyl amine hydrochloride (278 mg, 3.41 mmol) and 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester (175b) (150 mg, 0.341 mmol) to give a white solid (74 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1 H) 8.22 (d, J=1.77 Hz, 1 H) 7.27-7.31 (m, 1 H) 7.01-7.13 (m, 3 H) 6.78 (d, J=2.02 Hz, 1 H) 3.81 (s, 3 H) 3.16 (s, 3 H) 3.00 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C₂₃H₂₄FN₅O₄ m/z 454.20 (M+H⁺); Anal. Calcd. for C₂₃H₂₄FN₅O₄: C, 60.92; H, 5.33; N, 15.44; Found: C, 60.66; H, 5.37; N, 15.26.

Example 179 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid methyl ester

A mixture of 5-fluoro-pyridine-2-carboxylic acid methyl ester (179a) (342 mg, 2.20 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (633 mg, 2.20 mmol), and Cs₂CO₃ (1.44 g, 4.40 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H₂O, and extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried over Na₂SO₄ and concentrated. The residue was purified by Biotage column chromatography with 75-90% EtOAc in hexanes to give a white solid (524 mg, 56% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=3.03 Hz, 2 H) 8.13 (d, J=8.59 Hz, 1 H) 7.22-7.36 (m, 2 H) 7.06 (d, J=5.05 Hz, 2 H) 6.77 (d, J=2.27 Hz, 1 H) 4.01 (s, 3 H) 3.78 (s, 3 H) 2.89 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₂H₂₂N₄O₆ m/z 423.20 (M+H⁺).

Preparation of Intermediate 179a 5-Fluoro-pyridine-2-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 175a, from 5-fluoropicolinic acid (1.05 g, 7.44 mmol) to give a yellow solid (980 mg, 85% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=2.78 Hz, 1 H) 8.21 (dd, J=8.72, 4.42 Hz, 1 H) 7.55 (d, J=3.03 Hz, 1 H) 4.02 (s, 3 H); LCMS for C₇H₆FNO₂ m/z 156.00 (M+H⁺).

Example 180 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid

To a solution of 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid methyl ester (179) (524 mg, 1.24 mmol) in 10 mL THF was added 2 mL 1 N aqueous NaOH. The mixture was heated at 60° C. for 1 hr, and concentrated in vacuo. The residue was acidified to pH ˜1 with 1N aqueous HCl, filtered, washed with water, and dried under vacuum at 60° C. overnight to give an off-white solid (400 mg, 79% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (br. s., 1 H) 8.51 (br. s., 2 H) 7.97-8.17 (m, 1 H) 7.46-7.64 (m, 2 H) 7.23 (br. s., 2 H) 6.54 (br, s, 1 H) 3.76 (s, 3 H) 2.91 (s, 2 H) 1.44 (s, 6 H); LCMS for C₂₁H₂₀N₄O₅ m/z 409.20 (M+H⁺).

Example 181 4-(6-Cyano-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (634 mg, 2.76 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (396 mg, 1.33 mmol), Et₃N (0.96 mL, 6.89 mmol), and Cu(OAc)₂ (501 mg, 2.76 mmol) in CH₂Cl₂ (15 mL) was stirred at room temperature with 4 A molecular sieves for 4 days, then filtered through celite, washed with CHCl₃, concentrated, and purified by column chromatography with 30-60% EtOAc in hexanes to give a white foam (246 mg, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1 H) 8.45 (d, J=2.53 Hz, 1 H) 7.65 (d, J=8.59 Hz, 1 H) 7.21-7.35 (m, 2H) 7.10 (d, J=11.37 Hz, 2 H) 6.78 (d, J=2.02 Hz, 1 H) 3.73 (s, 3 H) 2.89 (s, 2 H)) 1.48 (s, 6 H); LCMS for C₂₁H₁₉N₅O₃ m/z 390.00 (M+H⁺).

Example 182 2,2-Dimethyl-4-(6-[1,2,4]oxadiazol-3-yl-pyridin-3-yloxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a suspension of 4-[6-(N-hydroxycarbamimidoyl)-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (182a) (63.4 mg, 0.15 mmol) in 3 mL trimethyl orthoformate was added 2 drops of boron trifluoride diethyl etherate. The resulting solution was stirred at 55° C. for 1 hr, concentrated, and purified by column chromatography with 60-70% EtOAc in hexanes to give a white solid (31 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1 H) 8.83 (s, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 8.14 (d, J=8.84 Hz, 1 H) 7.38 (dd, J=8.72, 2.91 Hz, 1 H) 7.27 (s, 1 H) 7.09 (s, 2 H) 6.79 (d, J=2.27 Hz, 1 H) 3.78 (s, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₂H₂₀N₆O₄ m/z 433.00 (M+H⁺); Anal. Calcd. for C₂₂H₂₀N₆O₄.0.4 CHCl₃: C, 56.03; H, 4.28; N, 17.50; Found: C, 56.03; H, 4.46; N, 17.07.

Preparation of Intermediate 182a 4-[6-(N-Hydroxycarbamimidoyl)-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 4-(6-cyano-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (181) in 3 mL EtOH was added 1 mL 50% NH₄OH in water. The resulting mixture was stirred at room temperature for 2 hr, concentrated in vacuo, dried under vacuum, and used as it is for the next step.

Example 183 4-(4-Cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (478 mg, 4.92 mmol) and 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (183a) (168 mg, 0.49 mmol) to give a white solid (176 mg, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1 H) 7.56 (dd, J=8.59, 7.33 Hz, 1 H) 7.16-7.32 (m, 1 H) 7.07 (d, J=3.03 Hz, 2 H) 6.68-6.83 (m, 3 H) 3.71 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C₂₂H₁₉FN₄O₃ m/z 407.00 (M+H⁺).

Preparation of Intermediate 183a 4-(4-Cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 161b, from 4-bromo-2-fluoro-benzonitrile (270 mg, 1.35 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (300 mg, 1.35 mmol) to give a white foam (336 mg, 73% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (dd, J=8.84, 7.33 Hz, 1 H) 7.28 (s, 1 H) 7.24 (d, J=1.26 Hz, 1 H) 6.81 (dd, J=8.34, 2.02 Hz, 1 H) 6.75 (dd, J=10.23, 2.40 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C₁₉H₁₆FNO₄ m/z 342.00 (M+H⁺).

Example 184 4-(4-Cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 2-methyl-2H-1,2,3-triazol-4-amine hydrochloride (662 mg, 4.92 mmol) and 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (183a) (168 mg, 0.49 mmol) to give a white solid (154 mg, 77% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1 H) 8.06 (s, 1 H) 7.57 (dd, J=8.59, 7.33 Hz, 1 H) 7.06-7.15 (m, 2 H) 6.67-6.88 (m, 2 H) 4.10 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₁H₁₈FN₅O₃ m/z 408.00 and 409.00 (M+H⁺).

Example 185 4-(3-Fluoro-4-[1,2,4]oxadiazol-3-yl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 182, from 4-[3-fluoro-4-(N-hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (185a) (178 mg, 0.40 mmol) to give white solid (82 mg, 45% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1 H) 8.76 (s, 1 H) 8.06 (t, J=8.34 Hz, 1 H) 7.25-7.30 (m, 1 H) 7.10 (d, J=2.02 Hz, 2 H) 6.71-6.93 (m, 3 H) 3.77 (s, 3 H) 2.90 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₃H₂₀FN₅O₄ m/z 450.00 and 451.00 (M+H⁺); Anal. Calcd. for C₂₃H₂₀FN₅O₄.0.4 H₂O: C, 60.49; H, 4.59; N, 15.34; Found: C, 60.31; H, 4.45; N, 15.49.

Preparation of Intermediate 185a 4-[3-Fluoro-4-(N-hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (183) (164 mg, 0.404 mmol) in 3 mL EtOH was added 1 mL 50% NH₄OH in water. The resulting mixture was stirred at 55° C. for 2 hr, concentrated in vacuo, dried under vacuum, and used as it is for the next step.

Example 186 4-(3-Fluoro-4-[1,2,4]oxadiazol-3-yl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 182, from 4-[3-fluoro-4-(N-hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide (186a) (162 mg, 0.368 mmol) to give a white solid (155 mg, 85% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.75-8.87 (m, 2 H) 8.00-8.10 (m, 2 H) 7.12 (d, J=2.27 Hz, 2 H) 6.86 (d, J=3.28 Hz, 2 H) 4.09 (s, 3 H) 2.91 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₂H₁₉FN₆O₄ m/z 451.20 and 452.00 (M+H⁺).

Preparation of Intermediate 186a 4-[3-Fluoro-4-(N-hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide (184) (150 mg, 0.368 mmol) and used without further purification for the next step.

Example 187 2,2-Dimethyl-4-(4-[1,2,4]oxadiazol-3-yl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 182, from 4-[4-(N-hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (187c) (135 mg, 0.321 mmol) to a give white solid (19 mg, 14% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1 H) 8.43 (s, 1 H) 8.08-8.13 (m, 2 H) 7.27 (s, 1 H) 7.07-7.11 (m, 2 H) 7.04 (d, J=4.29 Hz, 2 H) 6.78 (d, J=2.27 Hz, 1 H) 3.78 (s, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₃H₂₁N₅O₄ m/z 432.00 (M+H⁺).

Preparation of Intermediate 187a 4-(4-Cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 161b, from 4-bromo benzonitrile (246 mg, 1.35 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (300 mg, 1.35 mmol) to give a white foam (257 mg, 59% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.71 (m, 2 H) 7.20-7.30 (m, 2 H) 6.95-7.06 (m, 2 H) 3.88 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C₁₉H₁₇NO₄ m/z 324.00 (M+H⁺).

Preparation of Intermediate 187b 4-(4-Cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (366 mg, 3.96 mmol) and 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (187a) (128 mg, 0.396 mmol) to give a white solid (121 mg, 77% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1 H) 7.56-7.69 (m, 2 H) 7.21-7.33 (m, 1 H) 6.97-7.09 (m, 4 H) 6.79 (d, J=2.02 Hz, 1 H) 3.75 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₂H₂₀N₄O₃ m/z 389.20 (M+H⁺).

Preparation of Intermediate 187c 4-[4-(N-Hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (187b) (212 mg, 0.321 mmol) and used without further purification for the next step.

Example 188 2,2-Dimethyl-4-(4-[1,2,4]oxadiazol-3-yl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 182, from 4-[4-(N-hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide (188b) (141 mg, 0.334 mmol) to a give white solid (82 mg, 57% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 2 H) 7.96-8.16 (m, 3 H) 6.99-7.12 (m, 4 H) 4.06 (s, 3 H) 2.91 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₂H₂₀N₆O₄ m/z 433.20 (M+H⁺); Anal. Calcd. for C₂₂H₂₀N₆O₄.0.45 H₂O: C, 59.98; H, 4.78; N, 19.08; Found: C, 60.08; H, 4.64; N, 18.86.

Preparation of Intermediate 188a 4-(4-Cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 2-methyl-2H-1,2,3-triazol-4-amine hydrochloride (533 mg, 1.78 mmol) and 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (187a) (128 mg, 0.396 mmol) to give a white solid (130 mg, 84% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.82 (s, 1 H) 8.07 (s, 1 H) 7.62 (d, J=8.59 Hz, 2 H) 7.09 (d, J=10.36 Hz, 2 H) 7.02 (d, J=8.59 Hz, 2 H) 4.07 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₁H₁₉N₅O₃ m/z 390.20 (M+H⁺).

Preparation of Intermediate 188b 4-[4-(N-Hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide (188a) (130 mg, 0.334 mmol) and used without further purification for the next step.

Example 189 4-(3-Chloro-4-[1,2,4]oxadiazol-3-yl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 182, from 4-[3-Chloro-4-(N-hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (189c) (153 mg, 0.335 mmol) to a give white solid (37 mg, 24% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1 H) 8.81 (s, 1 H) 7.95 (d, J=8.59 Hz, 1 H) 7.27 (s, 1 H) 7.15 (d, J=2.53 Hz, 1 H) 7.10 (s, 2 H) 6.97 (dd, J=8.84, 2.53 Hz, 1 H) 6.80 (d, J=2.02 Hz, 1 H) 3.77 (s, 3 H) 2.90 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₃H₂₀ClN₅O₄ m/z 465.90, 466.90 and 467.80 (M+H⁺); Anal. Calcd. for C₂₃H₂₀ClN₅O₄.0.7 H₂O: C, 57.73; H, 4.51; N, 14.64; Found: C, 57.66; H, 4.51; N, 14.92.

Preparation of Intermediate 189a 4-(3-Chloro-4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 161b, from 4-bromo-2-chlorobenzonitrile (292 mg, 1.35 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (300 mg, 1.35 mmol) to give a white foam (116 mg, 24% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=8.59 Hz, 1 H) 7.25-7.34 (m, 1 H) 7.23 (d, J=1.01 Hz, 1 H) 7.04 (d, J=2.27 Hz, 1 H) 6.90 (dd, J=8.72, 2.40 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C₁₉H₁₆ClNO₄ m/z 380.00 (M+Na⁺).

Preparation of Intermediate 189b 4-(3-Chloro-4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (157 mg, 1.62 mmol) and 4-(3-chloro-4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (189a) (58 mg, 0.16 mmol) to give a white solid (53 mg, 77% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1 H) 7.91 (d, J=8.34 Hz, 2 H) 7.07 (dd, J=16.67, 8.34 Hz, 4 H) 6.78 (s, 1 H) 3.78 (s, 3 H) 2.90 (s, 2 H) 1.50 (s, 6 H); LCMS for C₂₂H₁₉ClN₄O₃ m/z 423.00 (M+H⁺).

Preparation of Intermediate 189c 4-[3-Chloro-4-(N-hydroxycarbamimidoyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(3-chloro-4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (189b) and used without further purification for the next step.

Example 190 7-Fluoro-4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 7-fluoro-4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190c). ¹H NMR (400 MHz, CDCl₃) δ 8.83 (d, J=13.64 Hz, 1 H) 7.89-7.94 (m, 2 H) 7.28-7.31 (m, 2 H) 7.06-7.12 (m, 2 H) 6.76 (d, J=2.27 Hz, 1 H) 3.84 (s, 3 H) 3.08 (s, 3 H) 2.97 (s, 2 H) 1.56 (s, 6 H); LCMS for C₂₂H₂₂FN₃O₅S m/z 460.20 (M+H)⁺; Anal. Calcd. for C₂₂H₂₂FN₃O₅S.0.83 H₂O: C, 55.69; H, 5.03; N, 8.86; Found: C, 55.69; H, 4.74; N, 8.63.

Preparation of Intermediate 190a 7-Fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and Intermediate 190b: 5-Fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

A mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (1.5 g, 6.7 mmol) and SelectFluoro (2.39 g, 6.75 mmol) in CH₃CN (10 mL) was heated to reflux overnight. The mixture was quenched with H₂O (100 mL) and extracted with CH₂Cl₂ (100 mL). The organic layer was dried over MgSO₄ and concentrated. The residue was purified by Biotage column chromatography, eluting with 5-25% EtOAc in hexanes to give a ˜1:1 mixture of starting material (3e) and 5-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190b) (810 mg) and 7-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190a) (372 mg, 23% yield) as a pale yellow color solid. ¹H NMR (for 190a) (400 MHz, CDCl3) δ 6.87 (d, J=4.29 Hz, 1 H) 5.23 (s, 1 H) 3.92 (s, 3 H) 3.04 (s, 2 H) 1.55 (s, 6 H); LCMS for C₂₂H₂₂FN₃O₅S m/z 241.20 (M+H)⁺

Preparation of Intermediate 190c 7-Fluoro-4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 7-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190a). ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.94 (m, 2 H) 7.10 (d, J=4.55 Hz, 1 H) 7.04-7.09 (m, 2 H) 3.92 (s, 3 H) 3.07 (s, 3 H) 2.92 (s, 2 H) 1.54 (s, 6 H); LCMS for C₂₂H₂₂FN₃O₅S m/z 395.00 (M+H)⁺.

Example 191 4-[4-(Azetidine-1-carbonyl)-phenoxy]-7-fluoro-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-[4-(azetidine-1-carbonyl)-phenoxy]-7-fluoro-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (191a). ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=13.39 Hz, 1 H) 7.61-7.65 (m, 2 H) 7.27-7.30 (m, 2 H) 6.96 (d, J=8.84 Hz, 2 H) 6.77 (d, J=2.27 Hz, 1 H) 4.34 (s, 2 H) 4.20-4.29 (m, 2 H) 3.81-3.86 (m, 3 H) 2.94 (s, 2 H) 2.32-2.40 (m, 2 H) 1.54 (s, 6 H); LCMS for C₂₅H₂₅FN₄O₄ m/z 465.00 (M+H)⁺; Anal. Calcd. for C₂₅H₂₅FN₄O₄.0.36 H₂O: C, 63.76; H, 5.50; N, 11.90; Found: C, 63.76; H, 5.46; N, 11.63.

Preparation of Intermediate 191a 4-[4-(Azetidine-1-carbonyl)-phenoxy]-7-fluoro-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 35b, from 7-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190a) and azetidin-1-yl-(4-bromo-phenyl)-methanone. ¹H NMR (400 MHz, CDCl₃) δ 7.61-7.65 (m, 2 H) 7.05 (d, J=4.55 Hz, 1 H) 6.94 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 4.27-4.37 (m, 2 H) 4.23 (s, 2 H) 3.90 (s, 3 H) 2.91 (s, 2 H) 2.32-2.40 (m, 2 H) 1.52 (s, 6 H); LCMS for C₂₂H₂₂FNO₅ m/z 400.20 (M+H)⁺.

Example 192 5-Fluoro-4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in two steps as described for Example 190, from 5-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190b) and purified by reverse phase HPLC to yield the desired compound. ¹H NMR (400 MHz, CD₃OD) δ 7.92-7.98 (m, 2 H) 7.48 (d, J=2.27 Hz, 1 H) 7.18 (d, J=8.84 Hz, 2 H) 6.92 (d, J=4.55 Hz, 1 H) 6.59 (d, J=2.27 Hz, 1 H) 3.80 (s, 3 H) 3.10 (s, 3 H) 2.92 (s, 2 H) 1.44 (s, 6 H); LCMS for C₂₂H₂₂FN₃O₅S m/z 460.00 (M+H)⁺; Anal. Calcd. for C₂₂H₂₂FN₃O₅S: C, 57.17; H, 4.86; N, 9.09; Found: C, 57.17; H, 5.04; N, 8.95.

Example 193 4-(1-Methanesulfonyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(1-methanesulfonyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193d). ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H) 8.09 (s, 1 H) 6.80 (d, J=1.01 Hz, 1 H) 6.70 (d, J=1.01 Hz, 1 H) 4.99-5.06 (m, 1 H) 4.33 (dd, J=9.60, 6.32 Hz, 2 H) 4.13 (s, 3 H) 4.07-4.12 (m, 2 H) 3.02 (s, 2 H) 2.93 (s, 3 H) 1.52 (s, 6 H); LCMS for C₁₉H₂₄N₄O₅S m/z 421.20 (M+H)⁺; Anal. Calcd. for C₁₉H₂₄N₄O₅S.0.23 H2O: C, 53.74; H, 5.81; N, 13.19; Found: C, 53.76; H, 5.87; N, 12.99.

Preparation of Intermediate 193a Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester

Methane sulphonyl chloride (0.5 mL, 6.43 mmol) was added to a solution of 1-(diphenylmethyl)-3-hydroxyazetidine (1.38 g, 5.77 mmol) and Et₃N (0.9 mL, 6.46 mmol) in toluene (10 mL) at 0° C. The reaction mixture was stirred and warmed to room temperature overnight. The mixture was quenched with H₂O (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried over MgSO₄ and concentrated to give pale yellow oil (756 mg, 41%) which was used without further purification.

Preparation of Intermediate 193b 4-(1-Benzhydryl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

Cs₂CO₃ (1.16 g, 4.95 mmol) was added to a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (193a) (756 mg, 2.38 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (440 mg, 1.98 mmol) in DMF (6 mL). The mixture was heated to 100° C. for 4 hr, quenched with H₂O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with H₂O, dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 30-40% EtOAc in hexanes to give a white sold (740 mg, 84% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J=7.07 Hz, 4 H) 7.27-7.32 (m, 4 H) 7.18-7.25 (m, 2 H) 7.04 (d, J=1.01 Hz, 1 H) 6.81 (d, J=1.01 Hz, 1 H) 4.87 (t, J=5.81 Hz, 1 H) 3.85 (s, 3 H) 3.76 (ddd, J=7.52, 5.87, 2.02 Hz, 2 H) 3.12 (ddd, J=7.33, 5.56, 1.77 Hz, 2 H) 2.99 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₈H₂₉NO₄ m/z 444.20 (M+H)⁺.

Preparation of Intermediate 193c 4-(Azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

Palladium on carbon (108 mg) was added to a solution of 4-(1-benzhydryl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193b) (740 mg, 1.67 mmol) in 1:1 EtOAc and MeOH. The mixture was stirred under H₂ balloon overnight. The mixture was filtered through Celite and concentrated to give a pale yellow solid (526 mg, 100% yield). LCMS for C₁₅H₁₉NO₄ m/z 278.10 (M+H)⁺.

Preparation of Intermediate 193d 4-(1-Methanesulfonyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

Et₃N (400 mg, 2.87 mmol) and methane sulfonyl chloride (75 uL, 0.97 mmol) were added to a solution of 4-(azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193c) (303 mg, 0.97 mmol) in CH₂Cl₂ (15 mL). The mixture was stirred at room temperature for 2 hr, quenched with 1N aqueous HCl (60 mL) and extracted with CH₂Cl₂ (60 mL). The organic layer was dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatograph to give a white solid (197 mg, 57% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.10 (s, 1 H) 6.75 (s, 1 H) 5.02 (d, J=6.06 Hz, 1 H) 4.34 (dd, J=8.46, 6.69 Hz, 2 H) 4.08 (dd, J=8.72, 4.93 Hz, 2 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 2.93 (s, 3 H) 1.50 (s, 6 H).

Example 194 4-(1-Methanesulfonyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(1-methanesulfonyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193d). ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H) 8.09 (s, 1 H) 6.80 (d, J=1.01 Hz, 1 H) 6.70 (d, J=1.01 Hz, 1 H) 4.99-5.06 (m, 1 H) 4.33 (dd, J=9.60, 6.32 Hz, 2 H) 4.13 (s, 3 H) 4.07-4.12 (m, 2 H) 3.02 (s, 2H) 2.93 (s, 3 H) 1.52 (s, 6 H); LCMS for C₁₈H₂₃N₅O₅S m/z 422.20 (M+H)⁺; Anal. Calcd. for C₁₈H₂₃N₅O₅S.0.10 EtOAc: C, 51.36; H, 5.58; N, 16.28; Found: C, 51.36; H, 5.71; N, 16.31.

Example 195 4-(1-Acetyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(1-acetyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (195a). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1 H) 8.09 (s, 1 H) 6.81 (d, J=1.01 Hz, 1 H) 6.69 (d, J=1.26 Hz, 1 H) 5.03 (dd, J=10.36, 2.53 Hz, 1 H) 4.57 (ddd, J=9.47, 6.19, 1.01 Hz, 1 H) 4.42 (dd, J=10.99, 6.69 Hz, 1 H) 4.06-4.18 (m, 5 H) 3.02 (s, 2 H) 1.92 (s, 3 H) 1.51 (s, 6 H); LCMS for C₁₉H₂₃N₅O₄ m/z 386.20 (M+H)⁺; Anal. Calcd. for C₁₉H₂₃N₅O₄.0.33 H₂O: C, 58.31; H, 6.09; N, 17.89; Found: C, 58.31; H, 6.06; N, 17.87.

Preparation of Intermediate 195a 4-(1-Acetyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

Et₃N (400 uL, 2.87 mmol) and acetyl chloride (70 uL, 0.99 mmol) were added to a solution of 4-(azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193c) (300 mg, 0.96 mmol) in CH₂Cl₂ (15 mL). The mixture was stirred at room temperature for 4 hr, then quenched with 1N aqueous HCl (80 mL), and extracted with CH₂Cl₂ (80 mL). The organic layer was dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 80% EtOAc in hexanes to give a colorless oil (239 mg, 73% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.12 (br. s., 1 H) 6.76 (br. s., 1 H) 5.03 (br. s., 1 H) 4.55 (br. s., 1 H) 4.43 (br. s., 1 H) 4.03-4.19 (m, 2 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.92 (s, 3 H) 1.51 (br. s., 6 H).

Example 196 4-(1-Acetyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 4-(1-acetyl-azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (195a). ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1 H) 7.30 (d, J=2.27 Hz, 1 H) 6.82 (s, 1 H) 6.80 (d, J=2.02 Hz, 1 H) 6.67 (d, J=1.26 Hz, 1 H) 5.01 (ddd, J=10.23, 6.44, 3.79 Hz, 1 H) 4.51-4.59 (m, 1 H) 4.42 (dd, J=10.74, 6.69 Hz, 1 H) 4.07-4.16 (m, 2 H) 3.81 (s, 3 H) 3.01 (s, 2 H) 1.91 (s, 3 H) 1.51 (s, 6 H); LCMS for C₂₀H₂₄N₄O₄ m/z 385.00 (M+H)⁺; Anal. Calcd. for C₂₀H₂₄N₄O₄.0.45 H₂O: C, 61.20; H, 6.39; N, 14.27; Found: C, 61.20; H, 6.32; N, 14.16.

Example 197 6-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 6-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197f). ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1 H) 7.53 (t, J=8.21 Hz, 1 H) 7.29 (d, J=2.27 Hz, 1 H) 6.85 (d, J=2.02 Hz, 1 H) 6.83 (dd, J=8.59, 2.27 Hz, 1 H) 6.77 (d, J=1.77 Hz, 1 H) 6.68 (dd, J=11.37, 2.27 Hz, 1 H) 6.59 (d, J=2.02 Hz, 1 H) 4.12-4.24 (m, 4 H) 3.81 (s, 3 H) 3.37 (s, 2 H) 2.34 (dt, J=15.41, 7.71 Hz, 2 H) 1.51 (s, 6 H); LCMS for C₂₅H₂₅FN₄O₄ m/z 465.20 (M+H)⁺; Anal. Calcd. for C₂₅H₂₅FN₄O₄.0.93 H₂O: C, 62.39; H, 5.63; N, 11.63; Found: C, 62.39; H, 5.49; N, 11.56.

Preparation of Intermediate 197a 4-Bromo-3,5-dihydroxy-benzoic acid methyl ester

To a solution of 4-bromo-3,5-dihydroxy-benzoic acid (450 g, 1.94 mol) in MeOH (3.5 L) was added drop wise conc. H₂SO₄ (20 mL) at room temperature, and the mixture was refluxed overnight. TLC (petroleum ether/EtOAc=1/1) showed the reaction was complete. MeOH was removed under vacuum to about 250 mL and the resulting solid was filtered. The filter cake was dried under vacuum to give the title compound (450 g, 94% yield) as a white solid

Preparation of Intermediate 197b 4-Bromo-3-hydroxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester

Na pieces (41.4 g, 1.82 mol) were added slowly to MeOH (3 L). The resulting mixture was stirred at room temperature for 30 min and then 4-bromo-3,5-dihydroxy-benzoic acid methyl ester (197a) (450 g, 1.82 mol) was added portion wise. The mixture was warmed to 60° C. 3-Chloro-2-methyl-propene (202.5 mL, 2 mol) was added drop wise. The mixture was refluxed for 6 h. TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (75 g, 13.6% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.27 (s, 1H), 7.06(s, 1H), 5.72(s, 1H), 5.11(s, 1H), 4.96(s, 1H), 4.47(s, 2H), 3.84(s, 3H), 1.79(s, 3H).

Preparation of Intermediate 197c 4-Bromo-3,5-dihydroxy-2-(2-methyl-allyl)-benzoic acid methyl ester

A solution of 4-bromo-3-hydroxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester (197b) (148 g, 0.49 mol) in NMP (1.5 L) was refluxed for 0.5 h. After TLC (petroleum ether/EtOAc=5/1) indicated complete consumption of 197b, the reaction mixture was cooled to room temperature and 20% aq. HCl was added until pH=1. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic phases were dried over Na₂SO₄ and concentrated to give a brown oil. The crude oil was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (139 g, 94% yield) as a white solid.

Preparation of Intermediate 197d 7-Bromo-6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester

To a stirred solution of 4-bromo-3,5-dihydroxy-2-(2-methyl-allyl)-benzoic acid methyl ester (197c) (85 g, 0.28 mol) in CH₂Cl₂ (1500 mL) was added drop wise BF₃.Et₂O (180 mL, 1.41 mol) at 0° C. The mixture was stirred at room temperature for 2 hr. After TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete, the reaction mixture was poured into water (1 L). The organic phase was separated and washed with saturated aqueous NaHCO₃, dried over Na₂SO₄ and concentrated to give a yellow solid. The crude solid was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (37 g, 44% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.07 (s, 1H), 5.43 (s, 1H), 3.80 (s, 3H), 3.29 (s, 2H), 1.45 (s, 6H)

Preparation of Intermediate 197e 6-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester

A suspension of 7-bromo-6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197d) (52 g, 0.17 mol) and 10% Pd on Carbon (5 g) in MeOH (1 L) was stirred under 50 Psi of H₂ at 35-40° C. for 3 days. After HPLC indicated complete consumption of 197d, the reaction mixture was filtered through Celite and the filtrate was concentrated to give the title compound (30.6 g, 79.6%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 6.93 (s, 1H), 6.39 (s, 1H), 5.32 (s, 1H), 3.81 (s, 3H), 3.17 (s, 2 H), 1.40 (s, 6H).

Preparation of Intermediate 197f 6-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 35b, from azetidin-1-yl-(4-bromo-2-fluoro-phenyl)-methanone and 6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197e). ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J=7.07 Hz, 1 H) 7.37 (d, J=1.77 Hz, 1 H) 7.29 (dd, J=9.35, 1.52 Hz, 1 H) 7.15 (d, J=2.27 Hz, 1 H) 6.62 (d, J=2.27 Hz, 1 H) 4.16-4.25 (m, 2 H) 4.07-4.16 (m, 2 H) 3.87-3.88 (m, 3 H) 3.33 (s, 2 H) 2.29-2.39 (m, 2 H) 1.51 (s, 6 H); LCMS for C₂₂H₂₂FNO₅ m/z 441.30 (M+H)⁺.

Example 198 6-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 6-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (198a). ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1 H) 8.08 (s, 1 H) 7.87-7.96 (m, 2 H) 7.13 (d, J=8.84 Hz, 1 H) 7.13 (q, J=4.80 Hz, 1 H) 6.86 (d, J=2.02 Hz, 1 H) 6.64 (d, J=2.02 Hz, 1 H) 4.12 (s, 3 H) 3.39 (s, 2 H) 3.08 (s, 3 H) 1.53 (s, 6 H); LCMS for C₂₁H₂₂N₄O₅S m/z 443.20 (M+H)⁺; Anal. Calcd. for C₂₁H₂₂N₄O₅S.0.70 H2O: C, 55.42; H, 5.18; N, 12.31; Found: C, 55.31; H, 4.90; N, 12.39.

Preparation of Intermediate 198a 6-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197e). ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, J=9.09 Hz, 2 H) 7.17 (d, J=2.27 Hz, 1 H) 7.10 (d, J=8.84 Hz, 2 H) 6.64 (d, J=2.02 Hz, 1 H) 3.89 (s, 3 H) 3.35 (s, 2 H) 3.06 (s, 3 H) 1.52 (s, 6 H); LCMS for C₁₉H₂₀O₅S m/z 377.20 (M+H)⁺.

Example 199 6-(4-Methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 6-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (198a). ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1 H) 7.91 (d, J=8.84 Hz, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 7.06-7.15 (m, 2 H) 6.85 (d, J=2.02 Hz, 1 H) 6.76 (d, J=2.02 Hz, 1 H) 6.62 (d, J=2.02 Hz, 1 H) 3.79 (s, 3 H) 3.38 (s, 2 H) 3.07 (s, 3 H) 1.52 (s, 6 H); LCMS for C₂₂H₂₃N₃O₅S m/z 442.20 (M+H)⁺; Anal. Calcd. for C₂₂H₂₃N₃O₅S.0.17 H₂O: C, 59.45; H, 5.32; N, 9.43; Found: C, 59.45; H, 5.32; N, 9.43.

Example 200 2-Hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200g) (422 mg, 1.0 mmol) in CH₂Cl₂ (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 3 hr, then concentrated and dried to give an off-white solid (424 mg, 100% yield) which was used without purification. To a solution of this crude solid (242 mg, 0.66 mmol) in DMF (5 mL) was added Et₃N (0.50 mL, 3.59 mmol), HATU (507 mg, 1.33 mmol) and 1-methyl-3-aminopyrazole (130 mg, 1.34 mmol). The reaction mixture was heated to 50° C. for 2 hr, quenched with H₂O (20 mL), and extracted with EtOAc (2×20 mL). The organic layers were washed with H₂O (2×40 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 0-3% CH₃OH in 1:1 EtOAc/CH₂Cl₂ to give a white solid (139 mg, 47% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1 H) 7.92 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 7.11-7.13 (m, 2 H) 7.09-7.11 (m, 1 H) 7.06 (d, J=1.52 Hz, 1 H) 6.77 (d, J=2.27 Hz, 1 H) 5.00-5.07 (m, 1 H) 3.88-3.98 (m, 1 H) 3.81 (s, 3 H) 3.75 (ddd, J=12.25, 6.06, 5.94 Hz, 1 H) 3.12-3.21 (m, 1 H) 3.09 (s, 3 H) 2.96-3.07 (m, 1 H); LCMS for C₂₁H₂₁N₃O₆S m/z 444.00 (M+H)⁺; Anal. Calcd. for C₂₁H₂₁N₃O₆S.0.34 H₂O: C, 56.13; H, 4.86; N, 9.06; Found: C, 56.08; H, 4.85; N, 9.05.

Preparation of Intermediate 200a 3,5-Bis-benzyloxy-4-bromo-benzoic acid benzyl ester

To a stirred solution of 4-bromo-3,5-dihydroxy-benzoic acid (350 g, 1.5 mol) in dry DMF (2 L) were added K₂CO₃ (725 g, 5.25 mL) and BnBr (769 g, 4.5 mol) in one portion. The mixture was stirred at room temperature for 2 days and then filtered. The filter cake was washed with CH₂Cl₂. The combined filtrates were concentrated to give the title compound (225 g, 40% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.22-7.52 (m, 17H), 5.38(s, 2H), 5.21 (s, 4H).

Preparation of Intermediate 200b 3,5-Bis-benzyloxy-4-bromo-benzoic acid

To a stirred solution of 3,5-bis-benzyloxy-4-bromo-benzoic acid benzyl ester (200a) (225 g, 0.45 mol) in THF (400 mL) and H₂O (500 mL) was added NaOH (89.4 g, 2.24 mol) in one portion. The mixture was refluxed for 4 hr. TLC (EtOAc/petroleum ether=1/4) showed that the reaction was complete. Et₂O (100 mL) was added to the mixture and the organic layer was separated. The aqueous layer was acidified with conc. HCl, and the resulting solid was filtered and dried in vacuo to give the title compound (150 g, 85% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.48 (dd, 4H), 7.39(t, 4H), 7.31 (m, 4H), 5.27(s, 4H).

Preparation of Intermediate 200c 3,5-Bis-benzyloxy-4-bromo-benzoic acid tert-butyl ester

To a stirred solution of 3,5-bis-benzyloxy-4-bromo-benzoic acid (200b) (153 g, 0.37 mol) in DMF (1 L) was added CDI (90 g, 0.56 mol) in several portions. The solution was stirred at 40° C. for 1 hr. t-BuOH (55 g, 0.74 mol) was added to the mixture and then followed by the drop wise addition of DBU (56.3 g, 0.37 mol). The resulting solution was stirred at 40° C. for 2 days. TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The mixture was cooled to room temperature and poured into ice water (1 L). The mixture was acidified to pH 5 with conc. HCl and stirred for 1 hr. The formed solid was filtered and washed with water, then dried in vacuo to give the title compound (165 g, 86% yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃): δ 7.57-7.25 (m, 12H), 5.21(s, 4H), 1.58 (s, 9H).

Preparation of Intermediate 200d 4-Allyl-3,5-bis-benzyloxy-benzoic acid tert-butyl ester

To a suspension of Mg pieces (5.76 g, 0.24 mol) in Et₂O (250 mL) was added catalytic I₂, followed by i-PrMgBr (19.7 g, 0.16 mol) in one portion. The mixture was irradiated with heating. After stirring for 2 hr, the resulting solution was added to THF (200 mL). n-BuLi (128 mL, 2.5 M in hexane, 0.32 mol) was added drop wise to the mixture at 0° C. The mixture was cooled to −78° C. and 3,5-bis-benzyloxy-4-bromo-benzoic acid tert-butyl ester (200c) (50 g, 0.107 mol) was added drop wise. After the mixture was stirred for 1 hr, CuCN (2.9 g, 0.032 mol), LiCl (2.7 g, 0.064 mol) and allyl bromide (51.5 g, 0.43 mol) were added sequentially. After stirring for another 30 min at −78° C., TLC (EtOAc/petroleum oil=1/10) showed the reaction was complete. The mixture was quenched with saturated aqueous NH₄Cl (150 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give the title compound (35 g, 76.4% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.57-7.25 (m, 12H), 5.98(m, 1H), 5.13 (s, 4H), 5.04-4.88 (m, 2H), 3.57 (m, 2H), 1.59 (s, 9H).

Preparation of Intermediate 200e 3,5-Bis-benzyloxy-4-oxiranylmethyl-benzoic acid tert-butyl ester

To a solution of 4-allyl-3,5-bis-benzyloxy-benzoic acid tert-butyl ester (200d) (125 g, 0.29 mol) in CH₂Cl₂ was added m-CPBA (100 g, 0.58 mol) in several portions. The mixture was refluxed overnight. The solid was filtered and washed with CH₂Cl₂. The combined filtrates were washed with saturated aqueous Na₂S₂O₄ (250 mL) and brine (250 mL). The organic layer was dried over Na₂SO₄ and concentrated to give a yellow oil. The crude oil was purified by flash column chromatography (EtOAc/petroleum ether=1/20) to give the title compound (75 g, 57.8%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.40 (m, 12H), 5.09(s, 4H), 3.53 (dd, 1H), 3.17 (m, 1H), 2.80 (dd, H), 2.63 (t, 1H), 2.51 (dd, 1H), 1.60 (s, 9H).

Preparation of Intermediate 200f 4-Hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

A mixture of 3,5-bis-benzyloxy-4-oxiranylmethyl-benzoic acid tert-butyl ester (200e) (55 g, 0.12 mol), 10% Pd on Carbon (5 g), Et₃N (15 g, 0.14 mol), and K₂CO₃ (20 g, 0.14 mol) in MeOH (250 mL) was stirred under 760 mmHg of H₂ at room temperature for 4 hr. TLC (EtOAc/petroleum oil=1/2) showed the reaction was complete. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/petroleum ether=1/3) to give the title compound (18 g, 55% yield) as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.12 (s, 1H), 6.94(s, H), 6.74 (s, 1H), 4.97 (m, 1H), 3.86 (m, 1H), 3.75 (m, 1H), 3.22 (m, 1H), 3.02 (m, 1H), 2.47 (s, 1H), 1.56 (s, 9H).

Preparation of Intermediate 200g 2-Hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The mixture of 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (921 mg, 3.46 mmol), 4-flurophenyl methylsulfone (602 mg, 3.46 mmol), and Cs₂CO₃ (2.37 g, 7.27 mmol) in DMF (6 mL) was heated to 120° C. for 5 hr. The mixture was quenched with H₂O (60 mL) and extracted with EtOAc (2×60 mL). The organic layers were washed with H₂O (2×80 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography eluting with 40-50% EtOAc in hexanes to give a colorless oil (1.05 mg, 72% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.91-7.99 (m, 2 H) 7.34 (t, J=6.69 Hz, 2 H) 7.09-7.17 (m, 2 H) 5.05 (d, J=2.78 Hz, 1 H) 3.88-3.97 (m, 1 H) 3.73-3.82 (m, 1 H) 3.14-3.23 (m, 1 H) 3.12 (s, 3 H) 3.07-3.11 (m, 1 H) 2.99 (dd, J=16.55, 7.20 Hz, 1 H) 1.62 (s, 9 H); LCMS for C₂₁H₂₄O₇S m/z 443.00 (M+Na)⁺.

Example 201 4-(4-Methanesulfonyl-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(4-methanesulfonyl-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (201a). ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1 H) 7.89-7.95 (m, 2 H) 7.28 (d, J=2.27 Hz, 1 H) 7.12 (t, J=2.02 Hz, 2 H) 7.09-7.11 (m, 1 H) 7.06 (d, J=1.52 Hz, 1 H) 6.77 (d, J=2.27 Hz, 1 H) 5.01-5.10 (m, 1 H) 3.80 (s, 3 H) 3.61 (d, J=4.80 Hz, 2 H) 3.43 (s, 3 H) 3.17 (dd, J=16.42, 9.60 Hz, 1 H) 3.08 (s, 3 H) 2.89-2.99 (m, 1 H); LCMS for C₂₂H₂₃N₃O₆S m/z 458.00 (M+H)⁺.

Preparation of Intermediate 201a 4-(4-Methanesulfonyl-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

NaH (50 mg, 60% in mineral oil, 1.3 mmol) was added to a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200g) (409 mg, 0.97 mmol) in THF (5 mL). The resulting mixture was stirred at 0° C. for 10 min and then methyl iodide (80 uL, 1.3 mmol) was added. The mixture was stirred at room temperature for 2 hr and then quenched with H₂O (20 mL), extracted with EtOAc (2×20 mL). The organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 20-30% EtOAc in hexanes to give a colorless oil (295 mg, 70% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.56 (s, 9 H) 2.89 (dd, J=16.55, 7.20 Hz, 1 H) 3.07 (s, 3 H) 3.08-3.17 (m, 1 H) 3.39-3.44 (m, 3 H) 3.58 (d, J=5.05 Hz, 2 H) 4.99-5.08 (m, 1 H) 7.04-7.10 (m, 2 H) 7.21 (d, J=1.01 Hz, 1 H) 7.30 (d, J=1.26 Hz, 1 H) 7.86-7.93 (m, 2 H); LCMS for C₂₂H₂₆O₇S m/z 457.00 (M+Na)⁺.

Example 202 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (202a). ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H) 7.52 (t, J=8.08 Hz, 1 H) 7.28 (s, 1 H) 7.05-7.14 (m, 2 H) 6.74-6.81 (m, 2 H) 6.68 (dd, J=10.99, 2.15 Hz, 1 H) 5.00 (ddd, J=12.76, 9.47, 3.03 Hz, 1 H) 4.18-4.25 (m, 2 H) 4.11-4.18 (m, 2 H) 3.89 (ddd, J=12.19, 6.25, 3.03 Hz, 1 H) 3.79 (s, 3 H) 3.73 (dt, J=12.13, 6.06 Hz, 1 H) 3.13 (dd, J=16.55, 9.47 Hz, 1 H) 2.92-3.01 (m, 1 H) 2.47 (t, J=6.32 Hz, 1 H) 2.29-2.38 (m, 2 H); LCMS for C₂₄H₂₃FN₄O₅ m/z 467.00 (M+H)⁺.

Preparation of Intermediate 202a 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. ¹H NMR (400 MHz, CDCl₃) δ 1.57 (s, 9 H) 2.26-2.38 (m, 2 H) 3.06-3.17 (m, 1 H) 3.67-3.78 (m, 1 H) 3.81-3.90 (m, 1 H) 4.09-4.18 (m, 3 H) 4.18-4.25 (m, 2 H) 4.92-5.02 (m, 1 H) 6.63-6.68 (m, 1 H) 6.78 (dd, J=8.59, 2.27 Hz, 1 H) 7.21 (d, J=1.26 Hz, 1 H) 7.49-7.56 (m, 1 H) 8.02 (s, 1 H); LCMS for C₂₄H₂₄FNO₆ m/z 444.00 (M+H)⁺.

Example 203 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (202a). ¹H NMR (400 MHz, CDCl₃) δ 8.41-8.85 (m, 1 H) 8.19-8.24 (m, 1 H) 8.11 (s, 1 H) 7.59 (dd, J=8.59, 1.77 Hz, 1 H) 7.54 (t, J=8.21 Hz, 1 H) 7.18 (d, J=1.01 Hz, 1 H) 7.11 (d, J=1.26 Hz, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.66-6.72 (m, 1 H) 4.98-5.06 (m, 1 H) 4.22 (t, J=7.83 Hz, 2 H) 4.16 (t, J=7.71 Hz, 2 H) 3.86-3.94 (m, 1 H) 3.75 (dd, J=12.38, 5.56 Hz, 1 H) 3.15 (dd, J=16.67, 9.60 Hz, 1 H) 2.93-3.01 (m, 1H) 2.31-2.34 (m, 5 H); LCMS for C₂₆H₂₄FN₃O₅ m/z 478.00 (M+H)⁺.

Example 204 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1 H) 7.54 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.13 (s, 1 H) 7.08 (s, 1 H) 6.81 (dd, J=8.59, 2.27 Hz, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 6.68 (dd, J=11.12, 2.27 Hz, 1 H) 5.00-5.08 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.16 (t, J=7.71 Hz, 2 H) 3.81 (s, 3 H) 3.60 (d, J=5.05 Hz, 2 H) 3.43 (s, 3 H) 3.15 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.42, 7.33 Hz, 1 H) 2.27-2.38 (m, 2 H); LCMS for C₂₅H₂₅FN₄O₅ m/z 481.00 (M+H)⁺.

Preparation of Intermediate 204a 4-Benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

Benzyl bromide (1.8 mL, 15.2 mmol) and Cs₂CO₃ (4.89 g, 15.0 mmol) were added to a solution of 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (4.0 g, 15.0 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with H₂O (60 mL) and extracted EtOAc (2×60 mL). The organic layers were washed with H₂O (2×100 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 30-40% EtOAc in hexanes to give a pale yellow oil (4.43 g, 83% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.45 (m, 5 H) 7.19 (s, 1 H) 7.09 (s, 1 H) 5.13 (s, 2 H) 4.96-5.03 (m, 1 H) 3.85 (ddd, J=12.00, 6.95, 3.28 Hz, 1 H) 3.74 (dt, J=12.13, 6.06 Hz, 1 H) 3.27 (dd, J=16.42, 9.60 Hz, 1 H) 3.01 (dd, J=16.42, 7.07 Hz, 1 H) 1.58 (s, 9 H); LCMS for C₂₁H₂₄O₅ m/z 357.00 (M+H)⁺.

Preparation of Intermediate 204b 4-Benzyloxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

NaH (134 mg, 3.35 mmol) was added to a solution of 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204a) (994 mg, 2.79 mmol) in THF (10 mL). The resulting mixture was stirred at 0° C. for 10 min and methyl iodide (210 uL, 3.37 mmol) was added. The mixture was stirred at room temperature for 2 hr, quenched with H₂O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 20-30% EtOAc in hexanes to give a colorless oil (295 mg, 70% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.45 (m, 5 H) 7.19 (d, J=1.01 Hz, 1 H) 7.11 (d, J=1.01 Hz, 1 H) 5.13 (s, 2 H)) 4.99-5.09 (m, 1 H) 3.54-3.64 (m, 2 H) 3.44 (s, 3 H) 3.23-3.33 (m, 1 H) 2.98 (dd, J=16.42, 7.33 Hz, 1 H) 1.57 (s, 9 H); LCMS for C₂₂H₂₆O₅ m/z 371.20 (M+H)⁺.

Preparation of Intermediate 204c 4-Benzyloxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-benzyloxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204b) and 1-methyl-3-aminopyrazole (268 mg, 2.95 mmol) to give a white solid (645 mg, 83% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1 H) 7.34-7.44 (m, 5 H) 7.29 (d, J=2.27 Hz, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 6.89 (s, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.12 (s, 2 H) 5.01-5.09 (m, 1 H) 3.79 (s, 3 H) 3.56-3.66 (m, 2 H) 3.45 (s, 3 H) 3.29 (dd, J=16.42, 9.60 Hz, 1 H) 3.01 (dd, J=16.42, 7.33 Hz, 1 H); LCMS for C₂₂H₂₃N₃O₄ m/z 394.00 (M+H)⁺.

Preparation of Intermediate 204d 4-Hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

10% Pd on Carbon (100 mg) was added to a solution of 4-benzyloxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204c) (640 mg, 1.63 mmol) in EtOAc (15 mL). The reaction mixture was stirred under H₂ balloon overnight. The mixture was filtered through Celite, washed with EtOAc and concentrated to give a white solid (508 mg, 100% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1 H) 7.96 (s, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 6.98 (s, 1 H) 6.82 (s, 1 H) 6.78 (d, J=2.27 Hz, 1 H) 4.98-5.07 (m, 1 H) 3.76 (s, 3 H) 3.56-3.65 (m, 2 H) 3.44 (s, 3 H) 3.25 (dd, J=15.92, 9.60 Hz, 1 H) 2.97 (dd, J=16.04, 7.20 Hz, 1 H); LCMS for C₁₅H₁₇N₃O₄ m/z 304.00 (M+H)⁺.

Example 205 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and 2,4-difluoro-N,N-dimethyl-benzamide. ¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.40 (t, J=8.21 Hz, 1 H) 7.26 (s, 1 H) 7.21 (s, 1 H) 7.00 (dd, J=11.12, 1.52 Hz, 1 H) 6.91 (dd, J=8.46, 1.89 Hz, 1 H) 6.54 (d, J=1.52 Hz, 1 H) 5.01-5.09 (m, 1 H) 3.76 (s, 3 H) 3.50-3.59 (m, 2 H) 3.29 (s, 3 H) 3.10-3.21 (m, 1 H) 2.99 (s, 3 H) 2.85-2.89 (m, 4 H); LCMS for C₂₄H₂₅FN₄O₅ m/z 469.20 (M+H)⁺; Anal. Calcd. for C₂₄H₂₅FN₄O₅.0.63 H2O: C, 60.08; H, 5.52; N, 11.68; Found: C, 60.08; H, 5.19; N, 11.53.

Example 206 (−)-4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and Example 207 (+)-4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compounds were prepared by the chiral separation of Example 205 by SFC column chromatography.

Example 206: [α]_(D)=−29.9; 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.12 (s, 1 H) 7.07 (d, J=1.26 Hz, 1 H) 6.82 (dd, J=8.46, 2.15 Hz, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 6.70 (dd, J=10.61, 2.27 Hz, 1 H) 5.01-5.08 (m, J=9.60, 7.26, 4.71, 4.71 Hz, 1 H) 3.81 (s, 3 H) 3.61 (d, J=5.05 Hz, 2 H) 3.43 (s, 3 H) 3.14-3.20 (m, 1 H) 3.13 (s, 3 H) 2.99 (d, J=1.77 Hz, 3 H) 2.93 (dd, J=16.42, 7.33 Hz, 1 H); LCMS for C₂₄H₂₅FN₄O₅ m/z 469.00 (M+H)⁺; Anal. Calcd. for C₂₄H₂₅FN₄O₅.0.55 H2O: C, 60.26; H, 5.50; N, 11.71; Found: C, 60.21; H, 5.33; N, 11.55.

Example 207: [α]_(D)=+35.7; 99.5% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.02 Hz, 1 H) 7.12 (s, 1 H) 7.07 (s, 1 H) 6.82 (dd, J=8.46, 2.15 Hz, 1 H) 6.77 (d, J=1.77 Hz, 1 H) 6.70 (dd, J=10.61, 2.27 Hz, 1 H) 5.01-5.08 (m, 1 H) 3.81 (s, 3 H) 3.61 (d, J=5.05 Hz, 2 H) 3.44 (s, 3 H) 3.14-3.20 (m, 1 H) 3.13 (s, 3 H) 2.99 (d, J=1.52 Hz, 3 H) 2.89-2.97 (m, 1 H); LCMS for C₂₄H₂₅FN₄O₅ m/z 469.00 (M+H)⁺; Anal. Calcd. for C₂₄H₂₅FN₄O₅.0.26 H₂O: C, 60.92; H, 5.44; N, 11.84; Found: C, 60.92; H, 5.32; N, 11.77.

Example 208 4-[4-(Azetidine-1-carbonyl)-phenoxy]-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and azetidin-1-yl-(4-fluoro-phenyl)-methanone. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1 H) 7.59-7.67 (m, 2 H) 7.28 (d, J=2.53 Hz, 1 H) 7.13 (d, J=1.26 Hz, 1 H) 7.06 (d, J=1.26 Hz, 1 H) 6.97-7.02 (m, 2 H) 6.79 (d, J=2.27 Hz, 1 H) 4.99-5.08 (m, 1 H) 4.29-4.39 (m, 2 H) 4.19-4.29 (m, 2 H) 3.80-3.82 (m, 3 H) 3.56-3.64 (m, 2 H) 3.44 (s, 3 H) 3.16 (dd, J=16.55, 9.47 Hz, 1H) 2.92 (dd, J=16.42, 7.33 Hz, 1 H) 2.31-2.41 (m, 2 H); LCMS for C₂₅H₂₆N₄O₅ m/z 463.20 (M+H)⁺.

Example 209 (−)-4-[4-(Azetidine-1-carbonyl)-phenoxy]-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and Example 210 (+)-4-[4-(Azetidine-1-carbonyl)-phenoxy]-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compounds were prepared by the chiral separation of Example 208 by SFC column chromatography.

Example 209: [α]_(D)=−29.72; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1 H) 7.58-7.70 (m, 2 H) 7.22-7.30 (m, 1 H) 7.09 (s, 1 H) 6.95-7.04 (m, 3 H) 6.77 (d, J=2.02 Hz, 1 H) 4.99-5.08 (m, 1 H) 4.35 (br. s., 2 H) 4.23 (d, J=9.09 Hz, 2 H) 3.80 (s, 3 H) 3.55-3.63 (m, 2 H) 3.44 (s, 3 H) 3.16 (dd, J=16.42, 9.60 Hz, 1 H) 2.84-2.95 (m, 1 H) 2.28-2.41 (m, 2 H); LCMS for C₂₅H₂₆N₄O₅ m/z 463.00 (M+H⁺).

Example 210: [α]_(D)=+28.85; ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1 H) 7.65 (d, J=8.84 Hz, 2 H) 7.23-7.31 (m, 1 H) 7.09 (s, 1 H) 6.96-7.06 (m, 3 H) 6.77 (d, J=2.27 Hz, 1 H) 5.04 (dd, J=4.55, 2.78 Hz, 1 H) 4.35 (br. s., 2 H) 4.24 (br. s., 2 H) 3.80 (s, 3 H) 3.54-3.66 (m, 2 H) 3.43 (s, 3 H) 3.15 (dd, J=16.67, 9.60 Hz, 1 H) 2.92 (dd, J=16.42, 7.33 Hz, 1 H) 2.29-2.42 (m, 2 H); LCMS for C₂₅H₂₆N₄O₅ m/z 463.00 (M+H⁺).

Example 211 4-(4-Dimethylcarbamoyl-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from and 3-amino-1-methyl-pyrazole and 4-(4-dimethylcarbamoyl-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (211b) to give a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1 H) 7.37-7.49 (m, 2 H) 7.23-7.30 (m, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 6.95-7.06 (m, 3 H) 6.77 (d, J=2.27 Hz, 1 H) 4.99-5.09 (m, 1 H) 3.81 (s, 3 H) 3.59-3.62 (m, 2 H) 3.45 (s, 3 H) 3.14-3.21 (m, 1 H) 3.06 (d, J=1.52 Hz, 6H) 2.93 (dd, J=16.55, 7.45 Hz, 1H); LCMS for C₂₄H₂₆N₄O₅ m/z 451.20 (M+H⁺).

Preparation of Intermediate 211a 4-(4-Dimethylcarbamoyl-phenoxy)-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluoro-N,N-dimethylbenzamide (989 mg, 5.91 mmol) and 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (1.500 g, 5.633 mmol) to give a white solid (154 mg, 7% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J=8.59 Hz, 2 H) 7.20 (d, J=16.17 Hz, 2 H) 6.96 (d, J=8.59 Hz, 2 H) 4.87-5.03 (m, 1 H) 3.77-3.87 (m, 1 H) 3.71 (br. s., 1 H) 2.99-3.13 (m, 7 H) 2.90 (dd, J=16.55, 7.20 Hz, 1 H) 1.54 (s, 9 H); LCMS for C₂₃H₂₇NO₆ m/z 358.20 (M-tBu+H)⁺.

Preparation of Intermediate 211b 4-(4-Dimethylcarbamoyl-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 204b, from 4-(4-dimethylcarbamoyl-phenoxy)-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (211a) and methyl iodide. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.43 (m, 2 H) 7.24 (d, J=1.26 Hz, 1 H) 7.17 (d, J=1.26 Hz, 1 H) 6.92-7.01 (m, 2 H) 4.92-5.05 (m, 1 H) 3.51-3.59 (m, 2 H) 3.41 (s, 3 H) 2.99-3.15 (m, 7 H) 2.81-2.90 (m, 1 H) 1.54 (s, 9 H); LCMS for C₂₄H₂₉NO₆ m/z 428.20 (M+H⁺).

Example 212 (+)-4-(4-Dimethylcarbamoyl-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and Example 213: (−)-4-(4-Dimethylcarbamoyl-phenoxy)-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compounds were prepared by the chiral separation of Example 211 by SFC column chromatography.

Example 212: [α]_(D)=+30.5; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1 H) 7.37-7.49 (m, 2 H) 7.22-7.30 (m, 1 H) 6.97-7.04 (m, 4 H) 6.77 (d, J=2.27 Hz, 1 H) 4.99-5.09 (m, 1 H) 3.81 (s, 3 H) 3.58-3.62 (m, 2H) 3.44 (s, 3 H) 3.13-3.21 (m, 1 H) 3.10 (br. s., 3 H) 3.06 (br. s., 3 H) 2.93 (dd, J=16.55, 7.45 Hz, 1 H); LCMS for C₂₄H₂₆N₄O₅ m/z 451.20 (M+H⁺).

Example 213 [α]_(D)=−33.9; ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1 H) 7.37-7.49 (m, 2 H) 7.23-7.30 (m, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 6.95-7.06 (m, 3 H) 6.77 (d, J=2.27 Hz, 1 H) 4.99-5.09 (m, 1 H) 3.81 (s, 3H) 3.59-3.62 (m, 2 H) 3.45 (s, 3 H) 3.14-3.21 (m, 1 H) 3.06 (d, J=1.52 Hz, 6H) 2.93 (dd, J=16.55, 7.45 Hz, 1 H); LCMS for C₂₄H₂₆N₄O₅ m/z 451.20 (M+H³⁰ ).

Example 214 4-Isopropoxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200 from 4-isopropoxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214c) and 1-methyl-3-aminopyrazole. ¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 1 H) 7.28-7.32 (m, 3 H) 7.05 (s, 1 H) 6.93-7.00 (m, 3 H) 6.89 (s, 1 H) 6.84 (s, 1 H) 5.19-5.27 (m, 1 H) 4.64-4.72 (m, 1 H) 4.20-4.26 (m, 1 H) 4.11 (dd, J=9.98, 4.67 Hz, 1 H) 3.82 (s, 3 H) 3.35 (dd, J=16.42, 9.35 Hz, 1 H) 3.11 (dd, J=16.55, 6.95 Hz, 1 H) 1.36 (d, J=5.81 Hz, 6 H); LCMS for C₂₃H₂₅N₃O₄ m/z 408.20 (M+H)⁺; Anal. Calcd. for C₂₃H₂₅N₃O₄.0.50 H2O: C, 66.33; H, 6.29; N, 10.09; Found: C, 66.29; H, 6.05; N, 9.87.

Preparation of Intermediate 214a 4-Benzyloxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

4-Benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204a) (414 mg, 1.16 mmol) was dissolved in CH₂Cl₂ (25 mL) and cooled to 0° C. whilst stirring under a N₂ atmosphere. The solution was treated with Ph₃P (457 mg, 1.74 mmol), phenol (164 mg, 1.74 mmol) and DIAD (350 uL, 1.78 mmol) added drop-wise. The resulting solution was stirred at room temperature for 2 hr. The reaction mixture was concentrated in vacuo and purified by column chromatography, eluting with 5-10% EtOAc in hexanes to give a colorless oil (480 mg, 95% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.46 (m, 5 H) 7.21-7.26 (m, 2 H) 7.11-7.14 (m, 1 H) 6.91-6.96 (m, 2 H) 6.83-6.87 (m, 1H) 5.17-5.27 (m, 1 H) 5.12-5.15 (m, 3 H) 4.17-4.23 (m, 1 H) 4.07-4.15 (m, 1 H) 3.40 (dd, J=16.67, 9.60 Hz, 1H) 3.15 (dd, J=16.67, 6.82 Hz, 1 H) 1.59 (s, 9 H); LCMS for C₂₇H₂₈C₅ m/z 433.00 (M+H)⁺.

Preparation of Intermediate 214b 4-Hydroxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

10% Pd on Carbon (50 mg) was added to a solution of 4-benzyloxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214a) (500 mg, 1.16 mmol) in EtOAc (10 mL). The mixture was stirred under H₂ balloon for 3 days. The mixture was filtered through Celite and concentrated to give a colorless oil (400 mg, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.32 (m, 2 H) 7.18 (s, 1 H) 7.04 (s, 1 H) 6.91-6.95 (m, 2 H) 6.85 (d, J=7.58 Hz, 1 H) 5.18-5.28 (m, 1 H) 4.09-4.17 (m, 2 H) 3.38 (dd, J=16.17, 9.60 Hz, 1 H) 3.15 (dd, J=16.29, 6.69 Hz, 1 H) 1.58 (s, 9 H); LCMS for C₂₀H₂₂O₅ m/z 365.00 (M+Na)⁺.

Preparation of Intermediate 214c 4-Isopropoxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

2-Iodopropane (174 mg, 1.02 mmol)) was added to a mixture of 4-hydroxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214b) (350 mg, 1.02 mmol) and K₂CO₃ (141 mg, 1.02 mmol) in DMF (5 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was diluted with H₂O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with H₂O (2×70 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatograph eluting with 5% EtOAc in hexanes to give a white solid (182 mg, 46% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.29 (d, J=1.26 Hz, 1 H) 7.22-7.26 (m, 1 H) 7.13 (s, 1 H) 7.07 (s, 1 H) 6.91-7.00 (m, 3 H) 6.85 (d, J=7.58 Hz, 1 H) 5.17-5.25 (m, 1 H) 4.59-4.68 (m, 1 H) 4.07-4.17 (m, 1 H) 3.34 (dd, J=16.55, 9.47 Hz, 1 H) 3.09 (dd, J=16.55, 6.95 Hz, 1 H) 1.58 (s, 9 H) 1.35 (d, J=6.06 Hz, 6 H); LCMS for C₂₃H₂₈O₅ m/z 385.20 (M+H⁺).

Example 215 2-Hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 2-hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (215a) and 3-amino-1-methyl-pyrazole. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1 H) 7.26-7.35 (m, 1 H) 6.95-7.05 (m, 1H) 6.76-6.86 (m, 2 H) 4.93-5.08 (m, 1 H) 4.59-4.71 (m, 1 H) 3.84-3.91 (m, 1 H) 3.83 (s, 3 H), 3.22 (dd, J=16.42, 9.60 Hz, 1 H) 2.89-3.02 (m, 1 H) 1.98 (t, J=6.44 Hz, 1 H) 1.35 (d, J=6.06 Hz, 6 H); LCMS for C₁₇H₂₁N₃O₄ m/z 332.20 (M+H⁺).

Preparation of Intermediate 215a 2-Hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

A mixture of 2-iodopropane (0.826 mL, 8.26 mmol), 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (2.00 g, 7.51 mmol), and K₂CO₃ (1.56 g, 11.3 mmol) in DMF (20 mL) was heated to 60° C. overnight. Additional 2-iodopropane (0.9 mL) and K₂CO₃ (0.9 g) were added. The resulting mixture was heated to 50° C. for 4 days, then cooled to room temperature, quenched with H₂O and extracted with 3×EtOAc. The organic layers were washed with 2×H₂O, dried over Na₂SO₄, and concentrated. The residue was purified by flash column chromatography with 50-70% EtOAc in hexanes to give a yellow syrup (2.0 g, 86% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.11 (s, 1 H) 7.03 (d, J=1.01 Hz, 1H) 4.90-5.05 (m, 1 H) 4.58-4.66 (m, 1 H) 3.81-3.88 (m, 1 H) 3.67-3.77 (m 1 H) 3.21 (dd, J=16.42, 9.60 Hz, 1 H) 2.94 (dd, J=16.42, 7.07 Hz, 1 H) 1.60 (s, 9 H) 1.32-1.34 (m, 6 H); LCMS for C₁₇H₂₄O₅ m/z 253.00 (M-tBu+H⁺).

Example 216 4-Isopropoxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in anhydrous MeOH (2 mL) was added NaOMe (1.4 mL, 25% wt). The mixture was stirred at room temperature overnight, then heated at 50° C. for 3 hr, concentrated, and purified by reverse phase HPLC to give a white glass (33 mg, 56% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1 H) 7.21-7.31 (m, 1 H) 7.00 (s, 1 H) 6.84 (dd, J=7.20, 1.64 Hz, 2 H) 5.01 (s, 1 H) 4.55-4.63 (m, 1 H) 3.75 (s, 3 H) 3.53-3.64 (m, 2 H) 3.44 (s, 3 H) 3.22 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.29, 7.45 Hz, 1 H) 1.32 (dd, J=6.06, 1.26 Hz, 6 H); LCMS for C₁₈H₂₃N₃O₄ m/z 346.20 (M+H⁺).

Preparation of Intermediate 216a Toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester

To a solution of 2-hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (215) (506 mg, 1.530 mmol) in pyridine (10 mL) was added DMAP (20 mg), followed by p-toluenesulfonyl chloride (533 mg, 2.79 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with 3×EtOAc, dried over Na₂SO₄, concentrated and purified by flash column chromatography with 35-60% EtOAc in hexanes to give a white solid (580 mg, 78% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H) 7.78 (d, J=8.34 H) 7.35 (d, J=8.08 Hz, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 6.96 (s, 1 H) 6.80 (d, J=2.27 Hz, 1 H) 6.69 (d, J=1.26 Hz, 1 H) 5.01 (dd, J=4.93, 1.89 Hz, 1 H) 4.56-4.66 (m, 1 H) 4.19 (dd, J=5.05, 2.27 Hz, 2 H) 3.81 (s, 3 H) 3.24 (dd, J=16.55, 9.73 Hz, 1 H) 2.95 (dd, J=16.42, 6.82 Hz, 1 H) 2.45 (s, 3 H) 1.30-1.35 (m, 6 H); LCMS for C₂₄H₂₇N₃O₆S m/z 486.20 (M+H⁺).

Example 217 2-Ethoxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in anhydrous EtOH (2 mL) was added NaOEt (1.5 mL, 21% wt). The mixture was heated at 50° C. for 4 hr, then quenched with H₂O and extracted with 3×EtOAc. The organic layers were washed with 2×H₂O, dried over Na₂SO₄, and concentrated. The residue was purified by reverse phase HPLC to give a white glass (22 mg, 36% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.99 (s, 1 H) 7.20-7.34 (m, 1 H) 7.02 (s, 1 H) 6.86 (dd, J=13.26, 1.64 Hz, 2 H) 4.92-5.09 (m, 1 H) 4.57-4.69 (m, 1 H) 3.78 (s, 3 H) 3.63-3.72 (m, 1 H) 3.54-3.62 (m, 3 H) 3.22 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.29, 7.45 Hz, 1 H) 1.34 (dd, J=5.81, 1.77 Hz, 6 H) 1.23 (t, J=7.07 Hz, 3 H); LCMS for C₁₉H₂₅N₃O₄ m/z 360.20 (M+H⁺).

Example 218 2-Dimethylaminomethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in THF (2 mL) was added dimethyl amine hydrochloride (190 mg) and triethylamine (0.4 mL). The mixture was heated at 50° C. for 2 days, then concentrated, and purified by reverse phase HPLC to give a white solid (6 mg, 10% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1 H) 7.25-7.32 (m, 1 H) 7.04 (s, 1 H) 6.90 (d, J=1.01 Hz, 1 H) 6.84 (d, J=2.27 Hz, 1 H) 5.03-5.14 (m, 1 H) 4.61-4.71 (m, 1 H) 3.81 (s, 3 H) 3.29 (dd, J=16.42, 9.35 Hz, 1 H) 2.75-2.92 (m, 2 H) 2.60-2.70 (m, 1 H) 2.47 (s, 6 H) 1.34 (d, J=6.06 Hz, 6 H); LCMS for C₁₉H₂₆N₄O₃ m/z 359.20 (M+H⁺).

Example 219 2-Cyclopropylaminomethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in THF (2 mL) was added aminopropane (0.5 mL). The mixture was heated at 50° C. for 2 days, then concentrated, and purified by reverse phase HPLC to give a white solid (10 mg, 16% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1 H) 7.26-7.34 (m, 1 H) 7.01 (s, 1 H) 6.80-6.87 (m, 1 H) 4.98-5.07 (m, 1 H) 4.59-4.69 (m, 1 H) 3.81 (s, 3 H) 3.23 (dd, J=16.42, 9.35 Hz, 1 H) 2.93-3.05 (m, 2 H) 2.86 (dd, J=16.42, 7.07 Hz, 1 H) 2.20-2.27 (m, 1 H) 1.34 (dd, J=5.94, 1.14 Hz, 6 H) 0.36-0.54 (m, 4 H); LCMS for C₂₀H₂₆N₄O₃ m/z 371.20 (M+H⁺).

Example 220 2-Benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid pyridin-2-ylamide

A mixture of 2-benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (220j) (0.5 g, 1.9 mmol), DIPEA (0.37 g, 2.85 mmol) and HATU (0.74 g, 1.94 mmol) in DMF (15 mL) was stirred at room temperature for 1 hr, and then pyridin-2-amine (0.18 g, 1.94 mmol) was added in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) indicated that the reaction was complete. The mixture was concentrated. The residue was purified by prep. HPLC to give the title compound (73 mg, 21% yield, TFA salt) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ11.71 (br, 1H), 8.76 (d, 1H), 8.27 (d, 1H), 8.14 (t, 1H), 7.17˜7.46 (m, 9H), 4.96 (d, 1H), 4.78 (t, 1H), 2.82 (m, 1H), 2.67 (m, 1H), 2.19 (m, 1H), 1.96 (m, 1H), 1.32 (d, 6H).

Preparation of Intermediate 220a 3,5-Bis-methoxymethoxy-benzoic acid methyl ester

To a suspension of methyl 3,5-dihydroxybenzoate (250 g, 1.5 mol) and K₂CO₃ (500 g, 3.6 mol) in MeCN (2 L) was added drop wise MOMCl (270 g, 3.35 mol) at 0° C. The mixture was stirred at room temperature for 1.5 hr. TLC (EtOAc/petroleum ether=1/2) showed that no starting material was present. The reaction mixture was filtered and the filtrate was concentrated to give a brown oil. The oil was suspended in CH₂Cl₂. The resulting solid was filtered off. The filtrate was concentrated again to give the title compound (200 g, 57%) as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ 7.36 (d, 2H), 6.91 (t, 1H), 5.19 (s, 4H), 3.90 (s, 3H), 3.47 (s, 6H).

Preparation of Intermediate 220b (3,5-Bis-methoxymethoxy-phenyl)-methanol

To a solution of 3,5-bis-methoxymethoxy-benzoic acid methyl ester (220a) (350 g, 1.37 mol) in THF (1.8 L) was added portion wise LiAlH₄ (62 g, 1.64 mol) at 0° C. The mixture was stirred at 0° C. for another 1 hr. TLC (EtOAc/petroleum ether=1/2) showed that the reaction was complete. The reaction was quenched with 2 N aqueous NaOH. The mixture was filtered through Celite. The filtrate was dried over Na₂SO₄ and concentrated to give the title compound (290 g, 76%) as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ 6.70 (d, 2H), 6.64 (d, 1H), 5.22 (s, 4H), 4.61 (s, 2H), 3.46 (s, 6H).

Preparation of Intermediate 220c (3,5-Bis-methoxymethoxy-benzyloxy)-tert-butyl-dimethyl-silane

To a solution of (3,5-bis-methoxymethoxy-phenyl)-methanol (220b) (290 g, 1.27 mol) and imidazole (129 g, 1.9 mol) in CH₂Cl₂ (1.5 L) was added TBSCl (286 g, 1.9 mol) at 5° C. in several portion was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) showed that the reaction was complete. The mixture was filtered and the filtrate was washed with water, dried over Na₂SO₄ and concentrated under high vacuum to give the title compound (320 g, 97%) as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ 6.68 (d, 2H), 6.57(t, 1H), 5.14 (s, 4H), 4.66 (s, 2H), 3.48 (s, 6H), 0.94 (s, 9H), 0.07 (s, 6H).

Preparation of Intermediate 220d [3,5-Bis-methoxymethoxy-44(E)-3-phenyl-allyl)-benzyloxy]tert-butyl-dimethyl-silane

To a suspension of NaH (60%, 18 g, 0.45 mol) in THF (2 L) were added (3,5-bis-methoxymethoxy-benzyloxy)-tert-butyl-dimethyl-silane (220c) (100 g, 0.3 mol) and TMEDA (81.6 g, 0.6 mol) in one portion. The mixture was stirred at 0° C. for 1 hr. n-BuLi (2.5 M in hexane, 180 mL, 0.45 mol) was added drop wise to the mixture at −20° C. and the solution was stirred for 1 hr. CuI (114 g, 0.6mol) was added in one portion and the reaction was stirred at −20° C. for another 1 hr. Then the mixture was added drop wise cinamy bromide (65 g, 0.3 mol) at −20° C. After stirring for another 30 min, TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The reaction mixture was quenched with H₂O (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×500mL). The organic layers were combined, washed with brine (1 L), dried over Na₂SO₄ and concentrated to give a dark oil. The crude oil was purified by column chromatography (EtOAc/petroleum ether=1/10) to give the title compound (55 g, 34%) as a yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.16˜7.41 (m, 5H), 6.82 (s, 2H), 6.47 (m, 2H), 5.22(s, 4H), 4.71 (s, 2H), 3.62 (d, 2H), 3.45 (s, 6H), 0.94 (s, 9H), 0.12 (s, 6H).

Preparation of Intermediate 220e [3,5-Bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-phenyl]-methanol

To a solution of [3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzyloxy]-tert-butyl-dimethyl-silane (220d) (55 g, 0.12 mol) in THF (250 mL) was added TBAF (47.2 g, 0.18 mol) in one portion. The mixture was stirred at room temperature for 0.5 hr. TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The reaction mixture was washed with brine (50 mL) and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in high vacuum to give the title compound (45 g, 92% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.16˜7.41 (m, 5H), 6.82 (s, 2H), 6.47 (m, 2H), 5.22(s, 4H), 4.71 (s, 2H), 3.62 (d, 2H), 3.45 (s, 6H).

Preparation of Intermediate 220f 3,5-Bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzaldehyde

To a solution of pyridine (62 g, 0.78 mol) in CH₂Cl₂ (500 mL) were added CrO₃ (39 g, 0.39 mol) and Silica gel (40 g) in several portions at 0° C. After stirring for 10 min, [3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-phenyl]-methanol (220e) (45 g, 0.13 mol) was added in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) indicated that the reaction was complete. The reaction mixture was filtered and the filter cake was washed with Et₂O. The combined filtrates were concentrated. The residue was suspended in Et₂O and filtered again. The filtrate was concentrated under vacuum to give the crude title compound (45 g, 100% yield) as a yellow oil, which was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl₃): δ 9.89 (s, 1H), 7.16-7.41 (m, 5H), 6.25˜6.44 (m, 2H), 5.36 (s, 4H), 3.66 (d, 2H), 3.47 (s, 6H).

Preparation of Intermediate 220g 3,5-Bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzoic acid

To a solution of 3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzaldehyde (220f) (42 g, 0.12 mol) in MeOH/H₂O (500 mL) was added AgNO₃ (21 g, 0.12 mol), followed by NaOH (15 g, 0.36 mol) in one portion at room temperature. The mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under vacuum to remove MeOH. The residue was extracted with Et₂O (2×100 mL) to remove impurities. The aqueous layer was acidified with conc. HCl to pH 4. The resulting white solid was filtered and dried under vacuum to give the title compound (31 g, 62% yield) as white solid.

Preparation of Intermediate 220h 3,5-Dihydroxy-4-((E)-3-phenyl-allyl)-benzoic acid methyl ester

To a solution of 3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzoic acid (220g) (18 g, 0.05 mol) in MeOH (300 mL) was added catalytic amount of conc. H₂SO₄ (3 mL) in one portion. The mixture was refluxed overnight. The solution was concentrated. The residue was dissolved in CH₂Cl₂ (75 mL) and washed with sat. NaHCO₃ (25 mL). The organic layers were dried and concentrated to give a brown solid (12 g, 73% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.63 (s, 2H), 7.11˜7.34 (m, 5H), 6.93 (s, 2H), 6.32 (s, 2H), 3.77 (s, 3H), 3.42 (s, 2H).

Preparation of Intermediate 220i 2-Benzyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester

A solution of 3,5-dihydroxy-4-((E)-3-phenyl-allyl)-benzoic acid methyl ester (220h) (12 g, 0.032 mol) in HCl (g)/MeOH (4 N, 150 mL) was stirred at room temperature for 2 days. The reaction solution was concentrated to give a brown solid. The crude solid was re-crystallized from EtOAc to give the product (7 g) as a yellow solid. The mother liquid was concentrated to give a brown solid (5 g). The total yield is 98%. ¹H NMR (400 MHz, CDCl₃): δ 9.90 (br, 1H), 7.27˜7.46 (m, 5H), 7.00 (s, 1H), 6.87 (s, 1H), 5.07 (d, 1H), 3.78 (s, 3H), 2.65 (d, 2H), 2.16 (m, 1H), 1.92 (m, 1H).

Preparation of Intermediate 220j 2-Benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid

To a mixture of 2-benzyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (220i) (5 g, 0.018 mol) and NaH (60%, 1.4 g, 0.035 mol) in DMF (15 mL) was added isopropyl bromide (3.3 g, 0.027 mol) in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) indicated that the reaction was complete. The mixture was quenched with H₂O (50 mL). The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated to give brown solid (6 g). The crude solid was purified by column chromatography (EtOAc/petroleum ether=1/4) to give the title compound (2 g, 32% yield) as white solid.

Example 221: 2-Benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 2-benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (220j) (0.5 g, 1.6 mmol) in CH₂Cl₂ (15 mL) were added 1-methyl-1H-pyrazol-3-ylamine (0.16 g, 1.7 mmol), EDCI (0.46 g, 2.4 mmol), HOBt (0.32 g, 2.4 mmol) and N-methylmorphiline (0.81 g, 8 mmol) sequentially. The mixture was stirred at room temperature overnight. The reaction solution was washed with water (5 mL), aq. HCl (1 N, 5 mL) and sat. NaHCO₃. The organic phase was dried over Na₂SO₄ and concentrated to give a yellow oil. The crude oil was purified by prep. HPLC to give the product as a white solid (98.6 mg, 16% yield, TFA salt). ¹H NMR (400 MHz, CDCl₃): δ 10.71 (s, 1H), 7.58 (s, 1H), 7.30-7.48 (m, 5H), 7.01˜7.19 (d, 2H), 6.57 (s, 1H), 5.08 (d, 1H), 4.74 (m, 1H), 3.74 (s, 3H), 2.66 (d, 2H), 2.17 (m, 1H), 1.96 (m, 1H), 1.28 (d, 6H).

Example 222: 4-Benzyloxy-2-difluoromethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 4-benzyloxy-2-formyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (222b) (500 mg, 1.32 mmol) in CH₂Cl₂ (3 mL) was added a solution of DAST (340 mg, 2.11 mmol) in CH₂Cl₂ (1.5 mL), and rinsed with CH₂Cl₂ (2 mL). The mixture was stirred at room temperature for 30 min. The reaction was quenched with H₂O, extracted with 3×CHCl₃, dried over Na₂SO₄, concentrated and purified by reverse phase HPLC to give a white solid (200 mg, 38% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s., 1 H) 7.39-7.45 (m, 2 H) 7.37-7.41 (m, 1 H) 7.34-7.40 (m, 2 H) 7.30 (d, J=2.27 Hz, 1 H) 7.14 (d, J=1.01 Hz, 1 H) 6.92 (d, J=1.01 Hz, 1 H) 6.83 (d, J=2.27 Hz, 1 H) 5.65-6.09 (m, 1 H) 5.11 (s., 2 H) 4.87-5.07 (m, 1 H) 3.76 (s., 3 H) 3.27-3.42 (m, 2 H); LCMS for C₂₁H₁₉F₂N₃O₃ m/z 400.00 (M+H)⁺.

Preparation of Intermediate 222a 4-Benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204a) and 3-amino-1-methyl-pyrazole to give a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1 H) 7.33-7.45 (m, 5 H) 7.30 (d, J=2.27 Hz, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 6.89 (d, J=1.01 Hz, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.12 (s, 2 H) 4.95-5.03 (m, 1 H) 3.81 (s, 3 H) 3.73-3.79 (m, 1 H) 3.27 (dd, J=16.17, 9.60 Hz, 1H) 3.03 (dd, J=16.29, 7.20 Hz, 1 H) 2.13 (t, J=6.44 Hz, 1 H); LCMS for C₂₁ H₂₁N₃O₄ m/z 380.00 (M+H⁺).

Preparation of Intermediate 222b 4-Benzyloxy-2-formyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a suspension of 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (222a) (1.05 g, 2.77 mmol) in CH₂Cl₂ (25 mL) was added Dess-Martin periodinane (1.41 g, 3.32 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO₃, extracted with 3×EtOAc, dried over Na₂SO₄, concentrated, and purified by flash column chromatography eluting with 55-100% EtOAc in hexanes to give a yellow foam (850 mg).

Example 223 4-[4-(Azetidine-1-carbonyl)-3,5-difluoro-phenoxy]-2-difluoromethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 33, from azetidin-1-yl)2,4,6-trifluorophenyl)methanone (57.4 mg, 0.267 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (75 mg, 0.24 mmol) to give a white solid (20 mg, 16% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1 H) 7.25-7.35 (m, 1 H) 7.12-7.21 (m, 2H) 6.71-6.82 (m, 1 H) 6.54 (d, J=8.34 Hz, 2 H) 5.73-6.12 (m, 1 H) 5.02 (d, J=8.08 Hz, 1 H) 4.23 (t, J=7.83 Hz, 2 H) 4.00-4.10 (m, 2 H) 3.78 (s, 3 H) 3.17-3.29 (m, 2 H) 2.36 (t, J=7.71 Hz, 2 H); LCMS for C₂₄H₂₀F₄N₄O₄ m/z 505.00 and 506.00 (M+H)⁺; Anal. Calcd. for C₂₄H₂₀F₄N₄O₄: C, 53.77; H, 4.01; N, 9.95; Found: C, 53.79; H, 3.91; N, 9.87.

Preparation of Intermediate 223a 2-Difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

10% Pd on Carbon (20 mg) was added to a solution of 4-benzyloxy-2-difluoromethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (222) (186 mg, 0.466 mmol) in EtOAc (5 mL). The mixture was stirred at room temperature with a H₂ balloon overnight, then filtered through Celite, washed with EtOAc, and concentrated to give yellow solid (143 mg, 99% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.44 (br. s., 1 H) 7.27 (br. s., 1 H) 7.07 (br. s., 1 H) 6.90 (br. s., 1 H) 6.79 (br. s., 1 H) 5.67-6.04 (m, 1 H) 4.94 (br. s., 1 H) 3.73 (br. s., 3 H) 3.14-3.37 (m, 2 H); LCMS for C₁₄H₁₃F₂N₃O₃ m/z 310.00 (M+H)⁺.

Example 224 2-Fluoromethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

A solution of 2,4,6-collidine (0.0311 mL, 0.235 mmol) and 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (200) (50 mg, 0.11 mmol) in CH₂Cl₂ (3 mL) was cooled to −15° C. DAST (0.0307 mL, 0.235 mmol) was added drop wise. The mixture was stirred at −15° C. to room temperature overnight, then quenched with MeOH at 0° C., concentrated, and purified by column chromatography eluting with 25-75% EtOAc in hexanes to give a white solid (9 mg, 18% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1 H) 7.78-8.03 (m, 2 H) 7.20-7.34 (m, 2 H) 7.02-7.20 (m, 3 H) 6.77 (d, J=2.27 Hz, 1 H) 5.01-5.19 (m, 1 H) 4.42-4.78 (m, 2 H) 3.79 (s, 3H) 3.25 (dd, J=16.55, 9.73 Hz, 1 H) 3.08 (s, 3 H) 2.99-3.06 (m, 1 H); LCMS for C₂₁H₂₀FN₃O₅S m/z 446.00 (M+H⁺).

Example 225 2-Difluoromethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 33, from 4-fluorophenyl methyl sulfone (28.2 mg, 0.162 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (50 mg, 0.160 mmol) to give a white solid (18 mg, 24% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1 H) 7.85-8.02 (m, 2 H) 7.22-7.38 (m, 2 H) 7.02-7.21 (m, 3 H) 6.77 (d, J=2.02 Hz, 1 H) 5.94 (t, 1 H) 5.02 (br. s., 1 H) 3.78 (s, 3 H) 3.55-3.65 (m, 1 H) 3.23-3.33 (m, 1 H) 3.09 (s, 3 H); LCMS for C₂₁H₁₉F₂N₃O₅S m/z 464.00 (M+H)⁺.

Example 226 4-[4-(Azetidine-1-carbonyl)-phenoxy]-2-difluoromethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 33, from azetidin-1-yl(4-fluorophenyl)methanone (57.4 mg, 0.32 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (99 mg, 0.32 mmol) to give a white solid (12 mg, 8% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1 H) 7.55-7.71 (m, 2 H) 7.22-7.31 (m, 1 H) 7.13-7.19 (m, 1 H) 7.06-7.12 (m, 1 H) 6.96-7.03 (m, 2 H) 6.79 (d, J=2.02 Hz, 1 H) 5.75-6.08 (m, 1 H) 4.93-5.19 (m, 1 H) 4.35 (br. s., 2 H) 4.24 (br. s., 2 H) 3.79 (s, 3 H) 3.57-3.63 (m, 1 H) 3.14-3.31 (m, 2 H) 2.30-2.42 (m, 1 H.); LCMS for C₂₄H₂₂F₂N₄O₄ m/z 469.00 (M+H)⁺.

Example 227 2-Hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofu ran-6-carboxylic acid tert-butyl ester (227d). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1 H) 7.91 (d, J=8.84 Hz, 2 H) 7.28 (d, J=2.02 Hz, 1 H) 7.11 (s, 1 H) 7.08 (d, J=2.53 Hz, 2 H) 7.05 (s, 1 H) 6.77 (d, J=1.77 Hz, 1H) 3.79 (s, 3 H) 3.75 (d, J=11.87 Hz, 1 H) 3.61 (d, J=11.87 Hz, 1 H) 3.20 (d, J=16.42 Hz, 1 H) 3.08 (s, 3H) 2.81 (d, J=16.42 Hz, 1H) 1.45 (s, 3 H); LCMS for C₂₂H₂₃N₃O₆S m/z 458.00 (M+H)⁺; Anal. Calcd. for C₂₂H₂₃N₃O₆S.0.48 TFA: C, 53.83; H, 4.62; N, 8.20; Found: C, 53.62; H, 4.85; N, 8.36.

Preparation of Intermediate 227a 3,5-Bis-benzyloxy-4-(2-methyl-allyl)-benzoic acid tert-butyl ester

To a suspension of Mg pieces (7.9 g, 0.23 mol) in THF (250 mL) was added a catalytic amount of I₂, followed by addition of i-PrMgBr (15 mL, 0.16 mol) drop wise. The mixture was heated slowly until refluxed violently. After stirring for 2 hr, the resulting mixture was added to THF (200 mL) and cooled to 0° C. n-BuLi (128 mL, 2.5 M in hexane, 0.32 mol) was added drop wise at 0° C. The mixture was cooled to −78° C. and 3,5-bis-benzyloxy-4-bromo-benzoic acid tert-butyl ester (200c) (50 g, 0.107 mol) was added drop wise. After the mixture was stirred for 1 hr, CuCN (2.85 g, 0.032 mol), LiCl (2.7 g, 0.064 mol), and 3-bromo-2-methyl-propene (43 mL, 0.43 mol) were added sequentially. After stirring for another 30 min at −78° C., TLC (EtOAc/petroleum ether=1/10) showed the reaction was complete. The mixture was quenched with saturated aqueous NH₄Cl (150 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give the title compound as a yellow oil (40 g, 84.4% yield).

Preparation of Intermediate 227b 3,5-Bis-benzyloxy-4-(2-methyl-oxiranylmethyl)-benzoic acid tert-butyl ester

To a solution of 3,5-bis-benzyloxy-4-(2-methyl-allyl)-benzoic acid tert-butyl ester (227a) (80 g, 0.18 mmol) in CH₂Cl₂ (500 mL) was added m-CPBA (62 g, 0.36 mol) portion-wise. The mixture was refluxed overnight. The solid was filtered and washed with CH₂Cl₂. The filtrate was washed with saturated aqueous Na₂S₂O₄ (250 mL) and brine (250 mL). The organic layer was separated, dried over Na₂SO₄ and concentrated to give a brown oil. The crude oil was quickly purified by column chromatography (EtOAc/petroleum ether=1/10) to give the title compound (40 g, 48.2% yield) as a white solid.

Preparation of Intermediate 227c 4-Hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

A mixture of 3,5-bis-benzyloxy-4-(2-methyl-oxiranylmethyl)-benzoic acid tert-butyl ester (227b) (158 g, 0.343 mol), 10% Pd/C (15 g), Et₃N (57.3 mL, 0.412 mol) and K₂Co₃ (56.94 g, 0.412 mol) in MeOH (1.5 L) was stirred under 760 mmHg of H₂ at room temperature overnight. TLC (EtOAc/petroleum ether=1/3) showed that the reaction was complete. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/petroleum ether=1/3) to give a brown oil. The brown oil was further purified by prep. HPLC to give the title compound (18 g, 18.7% yield) as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ 6.98 (s, 1H), 6.82(s, 1H), 3.67 (d, 1 H), 3.56 (d, 1H), 2.80 (d, 1H), 1.48 (s, 9H), 1.35 (s, 3H).

Preparation of Intermediate 227d 2-Hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 4-fluorophenyl methylsulfone. ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.94 (m, 2 H) 7.26-7.27 (m, 1 H) 7.22 (d, J=1.26 Hz, 1 H) 7.02-7.11 (m, 2 H) 3.69-3.76 (m, 1 H) 3.60 (dd, J=11.87, 7.58 Hz, 1 H) 3.16 (d, J=16.42 Hz, 1 H) 3.07 (s, 3 H) 2.78 (d, J=16.67 Hz, 1 H) 1.86 (dd, J=7.58, 5.81 Hz, 1 H) 1.57 (s, 9 H) 1.44 (s, 3 H); LCMS for C₂₆H₂₆O₇S m/z 435.00 (M+H)⁺.

Example 228 4-(4-Methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (228a). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1 H) 7.89-7.94 (m, 2 H) 7.28 (d, J=2.27 Hz, 1 H) 7.08-7.13 (m, 3 H) 7.05 (d, J=1.26 Hz, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 3.80 (s, 3 H) 3.42-3.52 (m, 2 H) 3.41 (s, 3 H) 3.15 (d, J=16.67 Hz, 1 H) 3.06-3.10 (m, 4 H) 1.47 (s, 3 H); LCMS for C₂₃H₂₅N₃O₆S m/z 472.00 (M+H)⁺.

Preparation of Intermediate 228a 4-(4-Methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 201a, from 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofu ran-6-carboxylic acid tert-butyl ester (227d) and methyl iodide. ¹H NMR (400 MHz, CDCl₃) δ 7.88-7.93 (m, J=9.47, 2.78, 2.40 Hz, 2 H) 7.28 (s, 1 H) 7.21 (d, J=1.26 Hz, 1 H) 7.04-7.10 (m, 2 H) 3.41-3.50 (m, 2 H) 3.40 (s, 3 H) 3.10 (d, J=16.67 Hz, 1 H) 3.07 (s, 3 H) 2.75 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H); LCMS for C₂₃H₂₈O₇S m/z 449.00 (M+H)⁺.

Example 229 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (229a). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.02 Hz, 1 H) 7.07 (d, J=7.83 Hz, 2 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.78 (d, J=2.02 Hz, 1 H) 6.70 (dd, J=10.61, 2.27 Hz, 1 H) 3.81 (s, 3 H) 3.69-3.76 (m, 1 H) 3.58-3.65 (m, 1 H) 3.19 (d, J=16.42 Hz, 1 H) 3.13 (s, 3 H) 2.93-3.01 (m, 4 H) 1.46 (s, 3 H); LCMS for C₂₄H₂₅FN₄O₅ m/z 469.00 (M+H)⁺.

Preparation of Intermediate 229a 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 2,4-difluoro-N,N-dimethyl-benzamide. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (t, J=8.08 Hz, 1 H) 7.24 (s, 1 H) 7.20 (d, J=1.26 Hz, 1 H) 6.78 (dd, J=8.59, 2.27 Hz, 1 H) 6.67 (dd, J=10.61, 2.27 Hz, 1 H) 3.67-3.73 (m, 1 H) 3.56-3.62 (m, 1 H) 3.08-3.18 (m, 4 H) 2.97 (d, J=1.52 Hz, 3 H) 2.77 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.43 (s, 3 H); LCMS for C₂₄H₂₈FNO₆ m/z 446.00 (M+H)⁺.

Example 230 2-Hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227d) and 5-methyl-pyridin-2-ylamine. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=8.84 Hz, 1 H) 8.05 (s, 1 H) 7.92 (d, J=8.84 Hz, 3 H) 7.28 (s, 1 H) 7.24 (s, 1 H) 7.15 (d, J=8.84 Hz, 2 H) 3.76 (d, J=11.87 Hz, 1 H) 3.62 (d, J=11.87 Hz, 1 H) 3.22 (d, J=16.67 Hz, 1 H) 3.07 (s, 3 H) 2.83 (d, J=16.67 Hz, 1 H) 2.42 (s, 3 H) 1.47 (s, 3 H); LCMS for C₂₄H₂₄N₂O₆S m/z 469.00 (M+H)⁺.

Example 231 4-(4-Methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (228a) and 5-methyl-pyridin-2-ylamine. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.92 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.65 (dd, J=8.59, 2.02 Hz, 1 H) 7.19 (s, 1 H) 7.13 (s, 2 H) 7.09-7.11 (m, 1 H) 3.43-3.53 (m, 2 H) 3.41 (s, 3 H) 3.16 (d, J=16.42 Hz, 1 H) 3.06-3.10 (m, 3 H) 2.80 (d, J=16.67 Hz, 1 H) 2.34 (s, 3 H) 1.48 (s, 3 H); LCMS for for C₂₅H₂₆N₂O₆S m/z 483.00 (M+H)⁺; Anal. Calcd. for C₂₅H₂₆N₂O₆S.0.37 TFA: C, 58.95; H, 5.18; N, 5.34; Found: C, 58.92; H, 5.07; N, 5.34.

Example 232 4-(3-Fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (232a) and 3-amino-1-methyl-pyrazole. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H) 7.80-7.99 (m, 1H) 7.26-7.32 (m, 1 H) 7.11 (dd, J=17.05, 1.39 Hz, 2 H) 6.73-6.92 (m, 3 H) 3.82 (s, 3 H) 3.75 (d, J=5.56 Hz, 1 H) 3.63 (d, J=7.58 Hz, 1 H) 3.23 (s, 3 H) 2.81 (d, J=16.17 Hz, 1 H) 2.04 (d, J=1.77 Hz, 1 H) 1.47 (s, 3 H); LCMS for C₂₂H₂₂FN₃O₆S m/z 476.00 (M+H⁺).

Preparation of Intermediate 232a Mixture of 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester and 4-(5-fluoro-2-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 2,4-difluorophenyl methyl sulfone. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (t, J=8.34 Hz, 1 H) 7.27-7.30 (m, 1H) 7.22 (d, J=1.01 Hz, 1 H) 6.85 (dd, J=8.84, 2.27 Hz, 1 H) 6.77 (dd, J=11.12, 2.27 Hz, 1 H) 3.66-3.76 (m, 1H) 3.51-3.63 (m, 1 H) 3.21 (s, 3 H) 3.16 (d, J=16.42 Hz, 1 H) 2.69-2.82 (m, 1H) 1.52-1.58 (m, 12 H); LCMS for C₂₂H₂₅FO₇S m/z 397.00 (M-tBu+H⁺).

Example 233 4-(3-Fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (232a) and 2-amino-5-picoline. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1 H) 8.22 (d, J=8.59 Hz, 1 H) 8.12 (d, J=2.02 Hz, 1 H) 7.93 (t, J=8.46 Hz, 1 H) 7.58 (dd, J=8.34, 2.02 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 7.13 (d, J=1.26 Hz, 1 H) 6.88 (dd, J=8.84, 2.27 Hz, 1 H) 6.82 (dd, J=10.86, 2.27 Hz, 1 H) 3.76 (d, J=5.56 Hz, 1 H) 3.64 (d, J=7.33 Hz, 1 H) 3.21 (s, 3 H) 2.81 (d, J=16.67 Hz, 1 H) 2.33 (s, 3 H) 1.97 (d, J=1.52 Hz, 1 H) 1.47 (s, 3 H); LCMS for C₂₄H₂₃FN₂O₆S m/z 487.00 (M+H⁺).

Example 234 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofu ran-6-carboxylic acid tert-butyl ester (234a). ¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.08 (s, 1 H) 7.06 (s, 1 H) 6.81 (dd, J=8.46, 2.15 Hz, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 6.69 (dd, J=10.61, 2.27 Hz, 1 H) 3.81 (s, 3 H) 3.41-3.51 (m, 2 H) 3.40 (s, 3 H) 3.13 (s, 3 H) 3.14 (d, J=16.42 Hz, 1 H) 2.98 (d, J=1.77 Hz, 3 H) 2.95-2.97 (m, 1 H) 1.47 (s, 3 H); LCMS for C₂₅H₂₇FN₄O₅ m/z 483.00 (M+H)⁺; Anal. Calcd. for C₂₅H₂₇FN₄O₅.0.49 H2O: C, 61.11; H, 5.74; N, 11.40, Found: C, 61.11; H, 5.68; N, 11.20.

Preparation of Intermediate 234a 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (229a) and methyl iodide. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (t, J=8.21 Hz, 1H) 7.26 (s, 1H) 7.20 (s, 1 H) 6.78 (dd, J=8.46, 1.89 Hz, 1 H) 6.66 (dd, J=10.74, 1.89 Hz, 1 H) 3.40-3.49 (m, 2 H) 3.39 (s, 3 H) 3.07-3.14 (m, 4 H) 2.97 (s, 3 H) 2.76 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.45 (s, 3 H); LCMS for C₂₅H₃₀FNO₆ m/z 482.00 (M+Na)⁺.

Example 235 4-(5-Fluoro-2-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared as a minor product to Example 232 from Intermediate 232a and purified by reverse phase HPLC. ¹H NMR (400 MHz, CDCl₃)) δ 8.38 (s, 1 H) 8.08 (dd, J=8.84, 6.06 Hz, 1 H) 7.26-7.31 (m, 1 H) 7.15 (d, J=4.80 Hz, 2 H) 6.90-7.01 (m, 1 H) 6.77 (d, J=2.27 Hz, 1 H) 6.61 (dd, J=9.47, 2.40 Hz, 1 H) 3.81 (s, 3 H) 3.72 (d, J=5.81 Hz, 1 H) 3.60 (s, 1 H) 3.29 (s, 3 H) 3.18 (d, J=16.42 Hz, 1 H) 2.84 (d, J=16.67 Hz, 1 H) 1.96 (d, J=1.52 Hz, 1 H) 1.45 (s, 3 H); LCMS for C₂₂H₂₂FN₃O₆S m/z 476.00 (M+H⁺).

Example 236 4-(5-Fluoro-2-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared as a minor product to Example 233 from Intermediate 232a and purified by reverse phase HPLC. ¹H NMR (400 MHz, CDCl₃)) δ 8.43 (s, 1 H) 8.23 (d, J=8.34 Hz, 1H) 8.05-8.16 (m, 2 H) 7.58 (dd, J=8.34, 2.02 Hz, 1 H) 7.21 (s, 2 H) 6.91-7.01 (m, 1 H) 6.61 (dd, J=9.47, 2.40 Hz, 1 H) 3.74 (dd, J=12.00, 5.68 Hz, 1 H) 3.61 (dd, J=11.87, 7.33 Hz, 1 H) 3.30 (s, 3 H) 3.19 (d, J=16.67 Hz, 1 H) 2.84 (d, J=16.67 Hz, 1 H) 2.33 (s, 3 H) 1.95 (t, J=6.57 Hz, 1 H) 1.46 (s, 3 H); LCMS for C₂₄H₂₃FN₂O₆S m/z 487.00 (M+H⁺).

Example 237 4-(3-Fluoro-4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (237a) and 3-amino-1-methyl-pyrazole. ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1 H) 7.92 (t, J=8.38 Hz, 1 H) 7.29 (d, J=2.26 Hz, 1 H) 7.12 (d, J=1.13 Hz, 1 H) 7.08 (d, J=1.13 Hz, 1 H) 6.88 (dd, J=8.76, 2.35 Hz, 1 H) 6.76-6.84 (m, 2 H) 3.81 (s, 3 H) 3.42-3.56 (m, 2 H) 3.41 (s, 3 H) 3.23 (s, 3 H) 3.15 (d, J=16.58 Hz, 1 H) 2.79 (d, J=16.58 Hz, 1 H) 1.48 (s, 3 H); LCMS for C₂₃H₂₄FN₃O₆S m/z 490.00 (M+H⁺).

Preparation of Intermediate 237a Mixture of 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester and 4-(5-fluoro-2-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 201a, from

Intermediate 232a and methyl iodide. ¹H NMR (400 MHz, CDCl3) δ 8.07 (dd, J=8.72, 6.19 Hz, 1 H) 7.89 (t, J=8.34 Hz, 1 H) 7.27-7.32 (m, 3 H) 7.21 (d, J=1.01 Hz, 1 H) 6.89-6.95 (m, 1 H) 6.85 (dd, J=8.84, 2.27 Hz, 1 H) 6.77 (dd, J=11.24, 2.40 Hz, 1 H) 6.57 (dd, J=9.85, 2.27 Hz, 1 H) 3.40-3.50 (m, 4 H) 3.39 (s, 3 H) 3.37 (s, 3 H) 3.31 (s, 3 H) 3.21 (s, 3 H) 3.11 (d, J=5.05 Hz, 1 H) 3.07 (d, J=5.05 Hz, 1 H) 2.77 (t, J=16.55 Hz, 2 H) 1.57 (s, 9 H) 1.56 (s, 9 H) 1.45 (s, 3 H) 1.44 (s, 3 H); LCMS for C₂₃H₂₇FO₇S m/z 422.00 (M-tBu+H⁺).

Example 238 4-(5-Fluoro-2-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared as a minor product to Example 237 from Intermediate 237a and purified by reverse phase HPLC. ¹H NMR (300 MHz, CDCl₃)) δ 8.55 (s, 1 H) 8.08 (dd, J=8.85, 6.22 Hz, 1 H) 7.26-7.32 (m, 1 H) 7.08-7.22 (m, 2 H) 6.87-7.01 (m, 1 H) 6.78 (d, J=2.26 Hz, 1 H) 6.61 (dd, J=9.70, 2.35 Hz, 1 H) 3.79 (s, 3 H) 3.46-3.54 (m, 2 H) 3.39 (s, 3 H) 3.30 (s, 3 H) 3.14 (d, J=16.58 Hz, 1 H) 2.82 (d, J=16.58 Hz, 1 H) 1.46 (s, 3 H); LCMS for C₂₃H₂₄FN₃O₆S m/z 490.00 (M+H⁺).

Example 239 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (229a) and 2-amino-5-methyl-pyridine. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1 H) 8.23 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.57 (dd, J=8.46, 1.89 Hz, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.13 (s, 1 H) 7.10 (s, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.71 (dd, J=10.61, 2.27 Hz, 1 H) 3.70-3.77 (m, 1 H) 3.57-3.66 (m, 1 H) 3.19 (d, J=16.67 Hz, 1 H) 3.13 (s, 3 H) 2.98 (d, J=1.52 Hz, 3 H) 2.81 (d, J=16.67 Hz, 1 H) 2.31 (s, 3H) 1.46 (s, 3 H); LCMS for C₂₆H₂₆FN₃O₅ m/z 480.00 (M+H)⁺.

Example 240 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (240a) and 2-amino-5-methyl-pyridine. ¹H NMR (400 MHz, CDCl₃) δ 9.01 (br. s., 1 H) 8.23 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.62 (dd, J=8.59, 1.77 Hz, 1 H) 7.53 (t, J=8.08 Hz, 1 H) 7.15 (s, 1 H) 7.11 (s, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.63-6.73 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.15 (t, J=7.71 Hz, 2 H) 3.74 (d, 1 H) 3.61 (d, J=11.87 Hz, 1 H) 3.18 (d, J=16.67 Hz, 1 H) 2.79 (d, J=16.67 Hz, 1 H) 2.28-2.38 (m, 5 H) 1.46 (s, 3 H); LCMS for C₂₇H₂₆FN₃O₅ m/z 492.00 (M+H)⁺.

Preparation of Intermediate 240a 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and azetidin-1-yl-(2,4-difluoro-phenyl)-methanone. ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.56 (m, 1 H) 7.24 (s, 1 H) 7.20 (d, J=1.26 Hz, 1 H) 6.77 (dd, J=8.59, 2.53 Hz, 1 H) 6.66 (dd, J=11.24, 2.40 Hz, 1 H) 4.21 (t, J=7.83 Hz, 2 H) 4.11-4.17 (m, 2 H) 3.65-3.74 (m, 1 H) 3.55-3.63 (m, 1 H) 3.13 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.34 (dt, J=15.60, 7.74 Hz, 2 H) 1.89-1.97 (m, 1 H) 1.56 (s, 9 H) 1.44 (s, 3 H); LCMS for C₂₅H₂₈FNO₆ m/z 458.20 (M+H)⁺.

Example 241 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (240a). ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1 H) 7.53 (t, J=8.21 Hz, 1 H) 7.32 (d, J=2.27 Hz, 1 H) 7.15 (s, 1 H) 7.11 (s, 1 H) 6.86 (d, J=2.27 Hz, 1 H) 6.81 (dd, J=8.59, 2.27 Hz, 1 H) 6.70 (dd, J=10.99, 2.15 Hz, 1 H) 4.22 (t, J=7.83 Hz, 2 H) 4.16 (t, J=7.58 Hz, 2 H) 3.84 (s, 3 H) 3.71-3.76 (m, 1 H) 3.59-3.64 (m, 1 H) 3.18 (d, J=16.42 Hz, 1 H) 2.80 (d, J=16.67 Hz, 2 H) 2.29-2.40 (m, 2 H) 1.46 (s, 3 H); LCMS for C₂₅H₂₅FN₄O₅ m/z 481.20 (M+H)⁺.

Example 242 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (242a). ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1 H) 7.53 (t, J=8.21 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.07 (d, J=9.35 Hz, 2 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.78 (d, J=2.27 Hz, 1 H) 6.67 (dd, J=11.12, 2.27 Hz, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.10-4.19 (m, 3 H) 3.80 (s, 3 H) 3.40 (s, 3 H) 3.12 (d, J'16.67 Hz, 1 H) 2.74-2.82 (m, 1 H) 2.29-2.38 (m, 2 H) 1.47 (s, 3 H); LCMS for C₂₆H₂₇FN₄O₅ m/z 495.20 (M+H)⁺; Anal. Calcd. for C₂₆H₂₇FN₄O₅.0.24 H₂O: C, 62.60; H, 5.55; N, 11.23; Found: C, 62.64; H, 5.67; N, 10.93.

Preparation of Intermediate 242a 4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (240a) and methyl iodide. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8.84 Hz, 2 H) 7.22 (s, 1 H) 7.07 (d, J=8.84 Hz, 2 H) 3.41-3.52 (m, 2 H) 3.40 (s, 3 H) 3.11 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.48 (td, J=7.89, 4.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H) 1.32-1.43 (m, 2 H) 1.00-1.12 (m, 2 H); LCMS for C₂₆H₃₀FNO₆ m/z 472.20 (M+H)⁺.

Example 243 (−)-4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and Example 244: (+)-4-[4-(Azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compounds were prepared by the chiral separation of Example 242 by SFC column chromatography.

Example 243: [α]_(D)=−20.49; 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1 H) 7.50-7.57 (m, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.07 (dd, J=11.24, 1.39 Hz, 2 H) 6.80 (dd, J=8.59, 2.53 Hz, 1 H) 6.78 (d, J=2.27 Hz, 1H) 6.67 (dd, J=11.12, 2.27 Hz, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.16 (t, J=7.71 Hz, 2 H) 3.81 (s, 3 H) 3.41-3.51 (m, 2 H) 3.39-3.41 (m, 3 H) 3.12 (d, J=16.42 Hz, 1 H) 2.78 (d, J=16.42 Hz, 1 H) 2.34 (dt, J=15.47, 7.80 Hz, 2 H) 1.47 (s, 3 H); LCMS for C₂₆H₂₇FN₄O₅ m/z 495.20 (M+H)⁺; Anal. Calcd, for C₂₆H₂₇FN₄O₅. 0.23 H₂O: C, 62.62; H, 5.55; N, 11.24; Found: C, 58.2862.61; H, 5.52; N, 11.25.

Example 244: [α]_(D)=+14.78; 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1 H) 7.53 (t, J=8.21 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.07 (d, J=9.85 Hz, 2 H) 6.76-6.85 (m, 2 H) 6.67 (dd, J=11.37, 2.27 Hz, 1 H) 4.19-4.26 (m, 2 H) 4.16 (t, J=7.71 Hz, 2 H) 3.81 (s, 3 H) 3.41-3.52 (m, 2 H) 3.40 (s, 3 H) 3.12 (d, J=16.42 Hz, 1 H) 2.77 (d, J=16.67 Hz, 1 H) 2.30-2.40 (m, 2 H) 1.47 (s, 3 H); LCMS for C₂₆H₂₇FN₄O₅ m/z 495.20 (M+H)⁺; Anal. Calcd. for C₂₆H₂₇FN₄O₅.0.20 H₂O: C, 62.69; H, 5.54; N, 11.25; Found: C, 62.76; H, 5.51; N, 11.14

Example 245 4-(4-Cyclopropanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(4-cyclopropanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (245a). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H) 7.84-7.91 (m, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 7.04-7.13 (m, 3 H) 3.81 (s, 3 H) 3.71-3.79 (m, 1 H) 3.62 (dd, J=11.87, 7.07 Hz, 1 H) 3.21 (d, J=16.42 Hz, 1 H) 2.87 (d, J=19.96 Hz, 1 H) 2.81 (s, 2 H) 2.44-2.53 (m, 1 H) 2.11 (t, J=6.44 Hz, 1 H) 1.6 (s, 3 H) 1.31-1.42 (m, 2 H) 1.01-1.11 (m, 2 H); LCMS for C₂₄H₂₅N₃O₆S m/z 484.20 (M+H)⁺; Anal. Calcd, for C₂₄H₂₅N₃O₆S.0.27 H₂O: C, 58.70; H, 5.04; N, 8.55; Found: C, 58.71; H, 5.19; N, 8.42.

Preparation of Intermediate 245a 4-(4-Cyclopropanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 1-cyclopropanesulfonyl-4-fluoro-benzene. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8.59 Hz, 2 H) 7.23 (s, 1H) 7.07 (d, J=8.59 Hz, 2 H) 3.73 (dd, J=11.87, 5.81 Hz, 1 H) 3.62 (d, J=7.58 Hz, 1 H) 3.16 (d, J=16.67 Hz, 1 H) 2.78 (d, J=16.67 Hz, 1 H) 2.48 (td, J=8.02, 4.67 Hz, 1 H) 1.55-1.58 (m, 12H) 1.45 (s, 2 H) 1.36 (dd, J=4.67, 1.89 Hz, 2 H) 0.97-1.13 (m, 2 H); LCMS for C₂₄H₂₇O₇S m/z 460.80 (M+H)⁺.

Example 246 4-(4-Cyclopropanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compound was prepared in a similar manner as described for Example 200, from 4-(4-cyclopropanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (245a). ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1 H) 8.08 (s, 1 H) 7.88 (d, J=8.84 Hz, 1 H) 7.82-7.92 (m, 1 H) 7.03-7.14 (m, 4 H) 4.12 (s, 3 H) 3.77 (dd, J=12.00, 5.68 Hz, 1 H) 3.63 (dd, J=12.00, 7.45 Hz, 1 H) 3.22 (d, J=16.42 Hz, 1 H) 2.83 (d, J=16.67 Hz, 1 H) 2.44-2.54 (m, 1 H) 1.96 (dd, J=7.45, 5.68 Hz, 1 H) 1.47 (s, 3 H) 1.37 (dd, J=4.80, 1.77 Hz, 2 H) 1.07 (dd, J=7.83, 2.02 Hz, 2H); LCMS for C₂₃H₂₄N₄O₆S m/z 485.00 (M+H)⁺; Anal. Calcd. for C₂₃H₂₄N₄O₆S.0.26 H₂O: C, 56.47; H, 5.05; N, 11.45; Found: C, 56.46; H, 5.00; N, 11.40.

Example 247 (−)-4-(4-Cyclopropanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and Example 248: (+)-4-(4-Cyclopropanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

The title compounds were prepared in a similar manner as described for Example 200, from 4-(4-cyclopropanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (247a), followed by chiral separation by SFC column chromatography.

Example 247: [α]_(D) =−−14.75; 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H) 7.85-7.90 (m, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 7.10-7.14 (m, 1 H) 7.09 (s, 2 H) 7.06 (d, J=1.26 Hz, 1 H) (d, J=2.27 Hz, 1 H) 3.81 (s, 3 H) 3.43-3.52 (m, 2 H) 3.41 (s, 3 H) 3.16 (d, J=16.67 Hz, 1 H) 2.80 (d, J=16.42 Hz, 1 H) 2.45-2.53 (m, 1 H) 1.48 (s, 3 H) 1.34-1.39 (m, 2 H) 1.07 (dd, J=7.83, 2.02 Hz, 2 H): LCMS for C₂₅H₂₇N₃O₆S m/z 498.20 (M+H)⁺; Anal. Calcd. for C₂₅H₂₇N₃O₆S: C, 60.35; H, 5.47; N, 8.45; Found: C, 60.34; H, 5.51; N, 8.37.

Example 248: [α]_(D)=+14.49; 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1 H) 7.87 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 7.10-7.12 (m, 1 H) 7.08-7.10 (m, 2 H) 7.06 (d, J=1.52 Hz, 1 H) 6.77 (d, J=2.27 Hz, 1 H) 3.81 (s, 3 H) 3.42-3.52 (m, 2 H) 3.41 (s, 3 H) 3.16 (d, J=16.67 Hz, 1 H) 2.80 (d, J=16.42 Hz, 1 H) 2.49 (ddd, J=8.02, 4.86, 3.03 Hz, 1 H) 1.48 (s, 3 H) 1.31-1.39 (m, 2 H) 1.07 (ddd, J=14.15, 6.32, 1.26 Hz, 2 H); LCMS for C₂₅H₂₇N₃O₆S m/z 498.20 (M+H)⁺; Anal. Calcd. for C₂₅H₂₇N₃O₆S. 0.16 H20: C, 60.00; H, 5.50; N, 8.40; Found: C, 60.01; H, 5.65; N, 8.38.

Preparation of Intermediate 247a 4-(4-Cyclopropanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester

The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-(4-cyclopropanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (245a) and methyl iodide. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8.84 Hz, 2 H) 7.22 (s, 1 H) 7.07 (d, J=8.84 Hz, 2 H) 3.41-3.52 (m, 2 H) 3.40 (s, 3 H) 3.11 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.48 (td, J=7.89, 4.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H) 1.32-1.43 (m, 2 H) 1.00-1.12 (m, 2 H); LCMS for C₂₅H₃₀O₇S m/z 475.20 (M+H)⁺.

Example 249 (+)-4-(4-Cyclopropanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide and Example 250: (+)-4-(4-Cyclopropanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide

The title compounds were prepared in a similar manner as described for Example 200, from 4-(4-cyclopropanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (247a), followed by chiral separation by SFC column chromatography.

Example 249: [α]_(D)=−11.16; 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1 H) 8.08 (s, 1 H) 7.82-7.94 (m, 2 H) 7.11 (d, J=9.09 Hz, 2 H) 7.09 (s, 2 H) 4.12 (s, 3 H) 3.42-3.56 (m, 2 H) 3.41 (s, 3 H) 3.17 (d, J=16.67 Hz, 1 H) 2.81 (d, J=16.42 Hz, 1 H) 2.37-2.60 (m, 1 H) 1.48 (s, 3 H) 1.37 (dd, J=4.80, 2.02 Hz, 2H) 1.07 (dd, J=7.83, 2.02 Hz, 2 H); LCMS for C₂₄H₂₆N₄O₆S m/z 499.00 (M+H)⁺; Anal. Calcd. for C₂₄H₂₆N₄O₆S: C, 57.82; H, 5.26; N, 11.24; Found: C, 57.70; H, 5.31; N, 11.11.

Example 250: [α]_(D)=+13.33; >99% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1 H) 8.08 (s, 1 H) 7.79-7.95 (m, 2 H) 7.05-7.14 (m, 4 H) 4.12 (s, 3 H) 3.42-3.55 (m, 2 H) 3.41 (s, 3 H) 3.17 (d, J=16.42 Hz, 1 H) 2.81 (d, J=16.67 Hz, 1 H) 2.45-2.54 (m, 1 H) 1.48 (s, 3 H) 1.37 (dd, J=4.55, 2.02 Hz, 2 H) 1.07 (dd, J=7.96, 1.89 Hz, 2 H); LCMS for C₂₄H₂₆N₄O₆S m/z 499.00 (M+H)⁺; Anal. Calcd. for C₂₄H₂₆N₄O₆S.0.09 H₂O: C, 58.82; H, 4.77; N, 11.43; Found: C, 58.88; H, 4.75; N, 11.33.

Example 251 2-Fluoromethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide

To a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (227) (62 mg, 0.140 mmol) and 2,4,6-collidine (0.0359 mL, 0.271 mmol) in dry CH₂Cl₂ was added trifluoromethanesulfonic acid anhydride (0.0365 mL, 0.217 mmol) at 0° C. The mixture was stirred at 0° C. to room temperature for 1 hr. TLC indicated that the reaction was complete. The reaction was quenched with 0.5 N aqueous HCl, extracted with 3×CHCl₃, dried over Na₂SO₄, and concentrated. The residue was dissolved in anhydrous CH₂Cl₂(3 mL), and TBAF (1 mL, 1 M in THF) was added. The resulting mixture was stirred at room temperature for 1.5 hr, quenched with H₂O, and extracted with 3×CHCl₃. The combined organic layer was dried over Na₂SO₄, concentrated, and purified by column chromatography eluting with 50-65% EtOAc in hexanes to give a white solid (18 mg, 28% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1 H) 7.84-7.96 (m, 2 H) 7.25-7.31 (m, 2 H) 7.02-7.15 (m, 3 H) 6.72-6.83 (m, 1 H) 4.26-4.54 (m, 2 H) 3.79 (s, 3H) 3.20 (d, J=16.67 Hz, 1H) 3.08 (s, 3 H) 2.89 (dd, J=16.67, 1.77 Hz, 1 H) 1.52 (s, 3 H); LCMS for C₂₂H₂₂FN₃O₅S m/z 460.00 (M+H⁺).

Example 252 2-Methyl-N-(5-methylpyridin-2-yl)-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxamide

2-Amino-5-methyl pyridine (289 mg, 2.67 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH₃)₂Cl (2.67 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 min at room temperature. Ethyl 2-methyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (100 mg, 0.267 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl₃, washed with brine and dried over MgSO₄. The crude product was purified by gradient silica gel chromatography using CHCl₃/MeOH (100/0 to 98/2) to give the title compound (100 mg, 86%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.32 (s, 3 H) 2.48 (s, 3 H) 3.07 (s, 3H) 6.24 (s, 1 H) 7.08-7.16 (m, 2 H) 7.48 (d, J=1.32 Hz, 1 H) 7.57 (dd, J=8.29, 2.35 Hz, 1 H) 7.81-7.97 (m, 3 H) 8.12 (d, J=2.35 Hz, 1 H) 8.25 (d, J=8.29 Hz, 1 H) 8.44 (s, 1 H). LCMS for C₂₃H₂₀N₂O₅S m/z 437.4 (M+H)⁺.

Preparation of Intermediate 252a 3-(Ethoxycarbonyl)-4-(5-methyl-2-furyl)but-3-enoic Acid

Sodium ethylate (74.2 g, 1.09 mol) was added under vigorous stirring to a solution of 5-methyl-2-furaldehyde 1 (100 g, 0.91 mol) and diethyl succinate (316 g, 1.81 mol) in ethanol (1 L). The reaction mixture was refluxed for 8 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 500 mL of a saturated aqueous solution of NaHCO₃, and shaken. The aqueous layer was separated, acidified with 10% HCl to pH 2, and subjected to extraction with 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give 45 g (0.19 mol, 21%) of the desired compound as a yellow solid.

Preparation of Intermediate 252b Ethyl 4-(Acetyloxy)-2-methyl-1-benzofuran-6-carboxylate

Sodium acetate (30 g, 0.36 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-2-furyl)but-3-enoic acid (45 g, 0.19 mol) in 250 mL of acetic anhydride. The reaction mixture was refluxed for 2 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The solid was washed with 200 mL of dichloromethane. The combined solutions were washed with 200 mL of a saturated aqueous solution of NaHCO₃ and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 3:1 as eluent to give 25 g (95 mmol, 51%) of desired compound as a yellow solid.

Preparation of Intermediate 252c Ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate

A mixture of ethyl 4-(acetyloxy)-2-methyl-1-benzofuran-6-carboxylate in absolute ethanol (500 mL) and potassium carbonate (18 g, 0.13 mol) was stirred for 3 h at 60° C. The mixture was diluted with 500 mL of dichloromethane and the suspension was filtered. The precipitate was washed with 200 mL of dichloromethane. The combined solutions was washed with 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The crude product introduced into a silica gel column and eluted with hexane/ethyl acetate mixture (2:1) to give 20 g (91 mmol, 95%) of desired compound as a yellow solid. ¹HNMR (DMSO d-6): 1.30 (t, 3H), 2.45 (s, 3H), 4.30 (qt, 2H), 6.65 (s, 1H), 7.28 (2, 1H) 7.53 (s, 1H), 10.25 (s, 1H).

Preparation of Intermediate 252d Ethyl 2-methyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate

The mixture of ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (4.5 g, 20.4 mmol), 1-fluoro-4-(methylsulfonyl)benzene (5.34 g, 30.7 mmol) and Cs₂CO₃ (9.99 g, 30.7 mmol) in DMF(10 mL) was heated in a microwave at 120° C. for 60 min. The sample was filtered and the filtrate was concentrated to give an oil residue. The oil was purified by HPLC to give the title compound (5.074 g, 66%) as an off-white solid. ¹H NMR (300 MHz, CHLOROFORM-D) d ppm 1.39 (t, J=7.16 Hz, 3 H) 2.46 (s, 3 H) 3.06 (s, 3H) 4.38 (q, J=7.16 Hz, 2 H) 6.21 (s, 1 H) 7.00-7.14 (m, 2 H) 7.62 (s, 1 H) 7.81-7.95 (m, 2 H) 8.01 (s, 1 H).

Examples 253-270 were prepared in a similar manner as described for Example 252, from Intermediate 252d and the appropriate amino heterocycles.

Example 253 2-Methyl-4-(4-(methylsulfonyl)phenoxy)-N-(5-(trifluoromethyl)-pyridin-2-yl)benzofuran-6-carboxamide

Example 254 N-(6,7-Dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)benzofuran-6-carboxamide

Example 255 2-Methyl-N-(5-methylisoxazol-3-yl)-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxamide

Example 256 N-(5-Fluoropyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)benzofuran-6-carboxamide

Example 257 2-Methyl-4-(4-(methylsulfonyl)phenoxy)-N-(pyridin-2-yl)-benzofuran-6-carboxamide

Example 258 N-(Isoxazol-3-yl)-2-methyl-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxamide

Example 259 N-(4-Methoxypyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxamide

Example 260 N-(5-chloropyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)benzofuran-6-carboxamide

Example 261 N-(5-cyanopyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)benzofuran-6-carboxamide

Example 262 N-(5-(Dimethylamino)pyrazin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxamide

Example 263 N-(5-methoxypyrazin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxamide

Example 264 Methyl 6-(2-methyl-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxamido)nicotinate

Example 265 N-(5-Ethylpyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)benzofuran-6-carboxamide

Example 266 N-(5-(Hydroxymethyl)pyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxamide

Example 267 2-Methyl-N-(2-methyl-2H-1,2,3-triazol-4-yl)-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxamide

Example 268 N-(6-(Hydroxymethyl)pyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxamide

Example 269 N-(6-(1-Hydroxyethyl)pyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxamide

Example 270 N-(5-ethoxypyridin-2-yl)-2-methyl-4-(4-(methylsulfonyl)-phenoxy)benzofuran-6-carboxamide

Example MW MF NMR m/z 253 490.5 C23H17F3N2O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 491.00 2.50 (s, 3 H) 3.03-3.18 (m, 3 H) 6.25 (s, 1 H) 7.05-7.20 (m, 2 H) 7.51 (d, J = 1.13 Hz, 1 H) 7.86-7.97 (m, 3 H) 8.02 (d, 1 H) 8.49 (d, 1 H) 8.58 (s, 1 H) 8.72 (s, 1 H) 254 462.5 C25H22N2O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 463.00 2.16 (d, J = 7.35 Hz, 2 H) 2.48 (s, 3 H) 2.87-3.03 (m, 4 H) 3.08 (s, 3 H) 6.25 (s, 1 H) 7.11 (d, J = 8.67 Hz, 2 H) 7.49 (s, 1 H) 7.60 (d, 1 H) 7.85-8.04 (m, 3 H) 8.14 (d, J = 8.29 Hz, 1 H) 8.50 (s, 1 H) 255 426.5 C21H18N2O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 427.00 2.43 (s, 3 H) 2.48 (s, 3 H) 3.09 (s, 3 H) 6.24 (s, 1 H) 6.85 (s, 1 H) 7.12 (d, J = 8.85 Hz, 2 H) 7.57 (s, 1 H) 7.90 (d, J = 8.85 Hz, 2 H) 7.98 (s, 1 H) 256 440.5 C22H17FN2O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 441.30 2.49 (s, 3 H) 3.07 (s, 3 H) 6.24 (s, 1 H) 7.05-7.19 (m, 2 H) 7.45-7.63 (m, 2 H) 7.84-8.01 (m, 3 H) 8.16 (d, J = 2.83 Hz, 1 H) 8.32-8.46 (m, J = 9.23, 4.14 Hz, 1 H) 8.57 (s, 1 H) 257 422.5 C22H18N2O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 423.40 2.49 (s, 3 H) 3.08 (s, 3 H) 6.25 (s, 1 H) 7.04-7.20 (m, J = 8.85 Hz, 3 H) 7.51 (d, J = 1.32 Hz, 1 H) 7.78 (s, 1 H) 7.88-8.03 (m, 3 H) 8.27-8.45 (m, 2 H) 8.58 (s, 1 H) 258 412.4 C20H16N2O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 413.40 2.50 (s, 3 H) 3.09 (s, 3 H) 6.26 (s, 1 H) 7.13 (d, J = 8.85 Hz, 2 H) 7.19-7.25 (m, 1 H) 7.50 (s, 1 H) 7.82-8.02 (m, 3 H) 8.33 (s, 1 H) 9.01 (s, 1 H) 259 452.5 C23H20N2O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 453.35 2.49 (s, 3 H) 3.02-3.18 (m, 3 H) 3.85-4.03 (m, 3 H) 6.26 (s, 1 H) 6.64 (dd, J = 5.65, 2.26 Hz, 1 H) 7.02-7.20 (m, 2 H) 7.49 (d, J = 1.13 Hz, 1 H) 7.86-7.98 (m, 3 H) 7.98-8.17 (m, 2 H) 8.63 (s, 1 H) 260 456.9 C22H17ClN2O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 457.20 2.49 (s, 3 H) 3.08 (s, 3 H) 6.25 (s, 1 H) 7.10 (d, J = 1.51 Hz, 1 H) 7.50 (d, J = 0.94 Hz, 1 H) 7.63 (d, J = 0.94 Hz, 1 H) 7.69-7.78 (m, 1 H) 7.84-7.96 (m, 2 H) 8.02 (s, 1 H) 8.26 (d, J = 2.45 Hz, 1 H) 8.37 (d, J = 8.85 Hz, 1H), 8.63 (s, 1H) 261 447.5 C23H17N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 448.20 2.48 (s, 3 H) 3.08 (s, 3 H) 6.26 (s, 1 H) 7.07-7.20 (m, 2 H) 7.54 (d, J = 1.32 Hz, 1 H) 7.87-8.04 (m, 3 H) 8.33-8.44 (m, 1 H) 8.48 (d, J = 8.67 Hz, 1 H) 8.93 (d, J = 1.70 Hz, 1 H) 9.07 (s, 1 H) 262 466.5 C23H22N4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 467.20 2.48 (s, 3 H) 3.08 (s, 3 H) 3.13 (s, 6 H) 6.25 (s, 1 H) 7.05-7.18 (m, 2 H) 7.49 (d, J = 1.13 Hz, 1 H) 7.71 (d, J = 1.51 Hz, 1 H) 7.84-8.01 (m, 3 H) 8.18 (s, 1 H) 9.15 (d, J = 1.32 Hz, 1 H) 263 453.5 C22H19N3O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 454.20 2.49 (s, 3 H) 2.99-3.23 (m, 3 H) 3.99 (s, 3 H) 6.25 (s, 1 H) 7.12 (d, J = 8.67 Hz, 2 H) 7.50 (s, 1 H) 7.81-8.08 (m, 4 H) 8.41 (s, 1 H) 9.19 (s, 1 H) 264 480.5 C24H20N2O7S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 481.20 2.44-2.61 (m, 3 H) 3.08 (s, 3 H) 3.95 (s, 3 H) 6.26 (s, 1 H) 7.07-7.20 (m, 2 H) 7.54 (d, J = 1.32 Hz, 1 H) 7.87-8.04 (m, 3 H) 8.33-8.44 (m, 1 H) 8.48 (d, J = 8.67 Hz, 1 H) 8.93 (d, J = 1.70 Hz, 1 H) 9.07 (s, 1 H) 265 450.5 C24H22N2O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 451.40 1.26 (t, J = 7.54 Hz, 3 H) 2.49 (s, 3 H) 2.65 (q, J = 7.72 Hz, 2 H) 3.08 (s, 3 H) 6.25 (s, 1 H) 7.12 (d, J = 8.67 Hz, 2 H) 7.50 (s, 1 H) 7.63 (s, 1 H) 7.84-8.03 (m, 3 H) 8.14 (s, 1 H) 8.28 (d, J = 8.48 Hz, 1 H) 8.54 (s, 1 H) 266 452.5 C23H20N2O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 453.20 2.48 (s, 3 H) 3.08 (s, 3 H) 4.72 (s, 2 H) 6.25 (s, 1 H) 7.03-7.20 (m, 2 H) 7.53 (s, 1 H) 7.78-7.87 (m, 1 H) 7.87-8.02 (m, 3 H) 8.41 (s, 2 H) 8.95 (s, 1 H) 11.85 (s, 1 H) 267 426.5 C20H18N4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 427.20 2.49 (s, 3 H) 3.08 (s, 3 H) 4.13 (s, 3 H) 6.25 (s, 1 H) 7.12 (d, J = 8.85 Hz, 2 H) 7.46 (s, 1 H) 7.85 (s, 1 H) 7.92 (d, J = 8.67 Hz, 2 H) 8.11 (s, 1 H) 8.49 (s, 1 H) 268 452.5 C23H20N2O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 453.30 2.47 (s, 3 H) 3.07 (s, 3 H) 5.29 (s, 2 H) 6.23 (d, J = 0.94 Hz, 1 H) 6.46 (d, J = 8.10 Hz, 1 H) 6.78 (d, J = 7.35 Hz, 1 H) 7.03-7.16 (m, 2 H) 7.45 (t, J = 7.82 Hz, 1 H) 7.68 (d, J = 1.13 Hz, 1 H) 7.85-7.98 (m, 2 H) 8.09 (s, 1H) 269 466.5 C24H22N2O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 467.20 1.52 (d, J = 6.59 Hz, 3 H) 2.50 (s, 3 H) 3.09 (s, 3 H) 3.70 (d, 1 H) 4.87 (d, J = 6.22 Hz, 1 H) 6.25 (d, J = 0.94 Hz, 1 H) 7.02-7.23 (m, 3 H) 7.54 (d, J = 1.32 Hz, 1 H) 7.79 (t, J = 7.91 Hz, 1 H) 7.88-8.02 (m, 3 H) 8.27 (d, J = 8.29 Hz, 1 H) 8.58 (s, 1 H) 270 466.5 C24H22N2O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 467.00 1.44 (t, J = 6.97 Hz, 3 H) 2.48 (s, 3 H) 3.07 (s, 3 H) 4.08 (q, J = 6.97 Hz, 2 H) 6.24 (s, 1 H) 7.06-7.22 (m, 2 H) 7.31 (dd, J = 9.04, 3.01 Hz, 1 H) 7.50 (s, 1 H) 7.87-8.10 (m, 4 H) 8.30 (d, J = 9.04 Hz, 1 H) 8.59 (s, 1 H)

Example 271 4-(4-(Methylsulfonyl)phenoxy)-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzofuran-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (0.273 g, 1.24 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (0.22 g, 1.26 mmol) in DMF (5 ML). The mixture was stirred at 120° C. for 8 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.18 g, 1.85 mmol) and HATU (0.7 g, 1.85 mmol) were added. The reaction mixture was stirred at 50° C. for one hour and then filtered. Purification by HPLC gave a solid (20 mg, 4% yield) as expected product. ¹H NMR (400 MHz, CD₃OD) δ 7.99 (m, 1 H) 7.93-7.96 (m, 2 H) 7.56 (m, 1 H) 7.50 (m, 1 H) 7.18-7.20 (m, 2 H) 6.59-6.60 (m, 1 H) 6.33 (s, 1 H) 3.83 (s, 3 H), 3.12 (s, 3 H), 2.47 (s, 3 H). LCMS for C₂₁H₁₉N₃O₅S m/z 426.10 (M+H)⁺.

Example 272 4-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzofuran-6-carboxamide

The title compound was prepared in a similar manner as described for Example 271, from ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (0.275 g, 1.25 mmol), 2,4-difluoro-N,N-dimethylbenzamide (0.289 g, 1.56 mmol) and 1-methyl-1H-pyrazol-3-amine (0.21 g, 2.12 mmol) in two steps to give a solid (5 mg, 1% yield) as expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1 H) 8.12 (s, 1H) 7.61-7.62 (m, 2 H) 7.38-7.42 (t, 1 H) 7.03-7.06 (m, 1 H) 6.88-6.91 (m, 1 H) 6.58-6.59 (m, 1 H) 6.50 (m, 1H) 3.78 (s, 3 H) 3.00 (s, 3 H) 2.88 (m, 3 H) 2.47-2.48 (m, 3 H). LCMS for C₂₃H₂₁FN₄O₄ m/z 437.20 (M+H)⁺.

Example 273 4-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-2-methyl-N-(5-methylpyridin-2-yl)benzofuran-6-carboxamide

The title compound was prepared in a similar manner as described for Example 271, from ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (0.275 g, 1.25 mmol), 2,4-difluoro-N,N-dimethylbenzamide (0.289 g, 1.56 mmol) and 2-amino-5-methyl pyridine (0.229 g, 2.1 mmol) in two steps to give an off-white solid (131 mg, 24% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1 H) 8.21 (m, 1 H) 8.16 (s, 1 H) 8.06-8.08 (d, 1 H)) 7.66 (m, 1 H) 7.64 (m, 1 H) 7.37-7.41 (t, 1 H) 7.02-7.06 (m, 1H) 6.89-6.92 (m, 1 H) 6.50 (s, 1 H) 2.99 (s, 3 H) 2.87 (m, 3 H) 2.47 (m, 3 H) 2.27 (s, 3 H).

Example 274 2-Ethyl-N-(5-methylpyridin-2-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

A solution of 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylic acid (300 mg, 0.83 mmol), HATU (476 mg, 1.3 mmol) and DIPEA (162 mg, 1.3 mmol) in DMF (20 mL) was stirred for 1 h. After which 5-methylpyridin-2-amine (108 mg, 1.0 mmol) was added. The resulting mixture was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC to afford the desired product (115.0 mg, 31%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.52 (s, 1H), 8.18 (d, 1H), 8.04 (s, 1H), 7.86 (d, 3H), 7.52 (d, 1H), 7.42 (s, 1H), 7.06 (d, 2H), 6.20 (s, 1H), 3.00 (s, 3H), 2.74 (q, 2H), 2.24 (s, 3H), 1.26 (t, 3H); MS (ACPI, pos): 451.2.

Preparation of Intermediate 274a (3E)-3-(Ethoxycarbonyl)-4-(5-ethyl-2-furyl)but-3-enoic acid

To a suspension of ^(t)BuOK (61.4 g, 0.54 mol) in ^(t)BuOH (180 mL) was added a suspension of 5-ethyl-2-furaldehyde (22.5 g, 0.18 mol) in succinic acid diethyl ester (142.1 g, 0.82 mol). The reaction mixture was refluxed for 1 h. Then the same amounts of ^(t)BuOK, ^(t)BuOH and succinic acid diethyl ester were added at the same temperature, and the reaction mixture was stirred at reflux for another 1 h. TLC (petroleum ether/EtOAc 2:1) indicated the complete consumption of the furaldehyde. The reaction mixture was allowed to cool to room temperature, acidified to a pH˜2 by 20% aqueous HCl (200 mL) and extracted with EtOAc (500 mL×3). The organic phase was washed with 10% aqueous Na₂CO₃ (500 mL×3). The combined aqueous layers was washed with ethyl ether (500 mL) and acidified to a pH˜2 with 20% aqueous HCl (100 mL). The aqueous phase was finally extracted with EtOAc (500 mL×4). The combined organic layers were dried over Na₂SO₄ and concentrated to give the crude acid (45.4 g, 100%), which was directly used to next step without further purification.

Preparation of Intermediate 274b Ethyl 4-(acetyloxy)-2-ethyl-1-benzofuran-6-carboxylate

A mixture of (ethoxycarbonyl)-4-(5-ethyl-2-furyl)but-3-enoic acid (45.4 g, 0.18 mol) and sodium acetate (59.0, 0.72 mol) in acetic anhydride (450 mL) was heated to reflux for 5 hours. TLC (petroleum ether/EtOAc 4:1) indicated complete consumption of the starting material. The reaction mixture was concentrated and the residue was poured into 15% aq. Na₂CO₃ (500 mL), and extracted with EtOAc (500 mL×3). The combined organic layers was washed with brine (200 mL), dried over Na₂SO₄, and concentrated. The product was purified via silica gel column chromatography using petroleum ether/EtOAc (70:1) to afford the desired compound (13.0 g, 28%) as a yellow solid.

Preparation of Intermediate 274c Ethyl 2-ethyl-4-hydroxy-1-benzofuran-6-carboxylate

A suspension of ethyl 4-(acetyloxy)-2-ethyl-1-benzofuran-6-carboxylate (8.0 g, 29.0 mmol) and K₂CO₃ (4.81 g, 34.8 mmol) in ethanol (80 mL) was refluxed for 24 hours. TLC (petroleum ether/EtOAc 4:1) showed complete consumption of the acetate. The solvent was removed under reduced pressure and the residue was poured into water (30 mL). The aqueous phase was acidified to pH˜2 with 10% aqueous HCl (50 mL) and extracted with EtOAc (100 mL×2). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc (40:1) to afford the desired compound (6.0 g, 88%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.87 (s, 1H), 7.45 (s, 1H), 6.46 (s, 1H), 6.36 (s, 1H), 4.34-4.27 (q, 2H), 2.77-2.71 (q, 2H), 1.40-1.31 (t, 3H), 1.31-1.21 (t, 3H).

Preparation of Intermediate 274d Ethyl 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate

A mixture of ethyl 2-ethyl-4-hydroxy-1-benzofuran-6-carboxylate (0.80 g, 3.4 mmol), 4-fluorophenyl methyl sulfone (0.60 g, 3.4 mmol) and Cs₂CO₃ (1.12 g, 3.4 mmol) in DMF (40 mL) was heated to 100° C. overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 4:1). The mixture was poured into water (50 mL) and extracted with EtOAc (90 mL×3). The organic layer was washed with brine (50 mL×2), dried over Na₂SO₄ and concentrated. The product was purified via column chromatography on silica gel eluted with petroleum ether/EtOAc (20:1) to afford the desired compound (0.80 g, 60%) as a colorless oil.

Preparation of Intermediate 274e 2-Ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylic acid

A mixture of ethyl 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (0.80 g, 2.1 mmol) and KOH (0.35 g, 6.3 mmol) in MeOH (40 mL) and water (4 mL) was heated to reflux overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 4:1). The reaction mixture was concentrated to dryness and poured into water (50 mL). The aqueous layer was acidified to pH˜2 with concentrated HCl (4 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with brine (50 mL×2), dried over Na₂SO₄ and concentrated to afford the desired compound (0.70 g, 94%) as an off-white solid.

Example 275 2-Ethyl-N-(1-methyl-1H-pyrazol-3-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-carboxamide

A solution of 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylic acid (400 mg, 1.1 mmol), HATU (635 mg, 1.6 mmol) and DIPEA (214 mg, 1.6 mmol) in DMF (20 mL) was stirred for 1 h. Then, 1-methyl-1H-pyrazol-3-amine (129 mg, 1.3 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na₂SO₄, concentrated and purified by preparative HPLC to afford the desired product (109.5 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, DMSO): δ 10.89 (s, 1H), 8.15 (s, 1H), 7.94 (d, 2H), 7.65 (s, 1H), 7.00 (s, 1H), 7.24 (d, 2H), 6.61 (s, 1H), 6.55 (d, 2H), 3.77 (s, 3H), 3.20 (s, 3H), 2.82 (q, 2H), 1.25 (t, 3H); MS (APCl, pos): 440.3.

Example 276 4-{4-[(Dimethylamino)carbonyl]phenoxy}-2-ethyl-N-(5-methylpyridin-2-yl)-1-benzofuran-6-carboxamide

A solution of 4-{4-[(dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylic acid (400 mg, 1.13 mmol), HATU (671 mg, 1.70 mmol) and DIPEA (226 mg, 1.70 mmol) in DMF (20 mL) was stirred for 1 h. Then 5-methylpyridin-2-amine (146 mg, 2.26 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na₂SO₄ and concentrated. The product was purified via preparative HPLC to afford the desired compound (133.7 mg, 27%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.92 (bs, 1H), 8.25 (d, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.55 (d, 2H), 7.44-7.37 (m, 3H), 6.96 (d, 2H), 6.22 (s, 1H), 3.10-2.93 (d, 6H), 2.74 (q, 2H), 2.26 (s, 3H), 1.26 (t, 3H). LCMS m/z 444.40 (M+H)⁺.

Preparation of Intermediate 276a 4-Iodo-N,N-dimethylbenzamide

A solution of 4-iodobenzoic acid (2.0 g, 8.0 mmol), HATU (4.6 g, 12.0 mmol) and DIPEA (1.6 g, 12.0 mmol) in DMF (30 mL) was stirred for 1 h. Then, dimethylamine hydrochloride (0.98 mg, 12.0 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 2:1). The reaction mixture was poured into water (30 mL) and extracted with EtOAc (40 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na₂SO₄ and concentrated. The product was purified by silica gel column chromatography using petroleum ether/EtOAc (4:1) to afford the desired compound (1.5 g, 60%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, 2H), 7.16 (d, 2H), 3.15-2.97 (d, 6H).

Preparation of Intermediate 276b Ethyl 4-{4-[(dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylate

A mixture of ethyl 2-ethyl-4-hydroxy-1-benzofuran-6-carboxylate (0.8 g, 3.4 mmol), 4-iodo-N,N-dimethylbenzamide (0.9 g, 3.3 mmol), Cs₂CO₃ (1.12 g, 3.4 mmol) and CuI (400 mg, 2.1 mmol) in pyridine (30 mL) was heated to 100° C. for 24 hours. TLC (petroleum ether/EtOAc 4:1) indicated the complete consumption of the phenol. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over Na₂SO₄ and concentrated. The product was purified via silica gel column chromatography using petroleum ether/EtOAc (20:1 to 1:1) to afford the desired compound (400 mg, 30%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.97 (s, 1H), 7.56 (s, 1H), 7.43 (d, 2H), 7.00 (d, 2H), 6.27 (s, 1H), 4.44-4.35 (q, 2H), 3.15-3.04 (d, 6H), 2.83-2.78 (q, 2H), 1.45-1.37 (t, 3H), 1.37-1.26 (t, 3H).

Preparation of Intermediate 276c 4-{4-[(Dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylic acid

A suspension of ethyl 4-{4-[(dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylate (400 mg, 1.0 mmol) and LiOH.H₂O (200 mg, 4.7 mmol) in MeOH (20 mL) and water (2 mL) was stir for 4 hr at room temperature. TLC (petroleum ether/EtOAc 4:1) indicated the reaction was complete. The reaction mixture was concentrated to dryness and poured into water (30 mL). The aqueous layer was acidified to pH˜2 with conc. HCl and extracted with EtOAc (20 mL×3). The organic layer was washed with brine (25 mL×2), dried over Na₂SO₄ and concentrated to afford the desired product (350 mg, 99%) as a yellow solid.

Example 277 N,N-Dimethyl-5-[(2-methyl-6-{[(5-methylpyridin-2-yl)amino]-carbonyl}-1-benzofuran-4-yl)oxy]pyridine-2-carboxamide

To a solution of 5-methylpyridin-2-amine (191 mg, 1.76 mmol) in DCE at 0° C. was added Al(CH₃)₂Cl drop-wise. After stirring the mixture at room temperature for 20 minutes ethyl 4-({6-[(dimethylamino)carbonyl]pyridin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (65 mg, 0.18 mmol) was added. The reaction was stirred at room temperature for 14 hours. The sample was diluted with CH₂Cl₂ and quenched with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL). Caution, addition was done slowly. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The crude sample was introduced into a silica gel column and eluted with MeOH/CHCl₃ (3/97) to provide the product (35 mg, 85% yield) as white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.32 (s, 3 H) 2.48 (s, 3 H) 3.16 (d, J=7.54 Hz, 6 H) 6.26 (s, 1 H) 7.31 (dd, J=8.67, 2.83 Hz, 1 H) 7.48 (d, J=1.13 Hz, 1 H) 7.58 (d, J=6.78 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 7.87 (s, 1 H) 8.12 (s, 1 H) 8.26 (d, J=8.48 Hz, 1 H) 8.38 (e, J=2.64 Hz, 1H) 8.53 (s, 1 H); MS (ESI, pos): 431.

Preparation of Intermediate 277a 5-Bromo-N,N-dimethylpyridine-2-carboxamide

To a solution of 5-bromopyridine-2-carboxylic acid (1.5 g, 7.4 mmol), dimethyl amine (1.3 gm, 16 mmol), diisopropylethyl amine (excess) in DMF (10 mL) was added a solution of HATU in DMF (5 mL). After stirring the reaction for 14 hours at room temperature, the solvent was removed under reduced vacuum. The residue was taken up in ethyl acetate, washed with 1 N HCl (2x), brine (2×), 1 N NaOH (2×), brine (3×), dried over MgSO₄, and concentrated. The crude was product was used in subsequent steps without further purification.

Preparation of Intermediate 277b 5-Bromo-N,N-dimethylpyridine-2-carboxamide 1-oxide

To a solution of 5-bromo-N,N-dimethylpyridine-2-carboxamide (730 mg, 3.19 mmol) in 10 mL of HOAc was added 1 ml of 35% H₂O₂. After stirring the mixture at 78° C. for 14 hours, it was cooled and concentrated under reduced pressure. The residue was made alkaline with excess solid Na₂CO₃ and diluted with 25 mL of CHCl₃ with stirring. The inorganic salts were filtered off, and the organic layer was dried over Na₂SO₄. The solvent was evaporated under reduced pressure to provided the product (750 mg, 98%), which was used without further purification. MS (ESI, pos): 247.00.

Preparation of Intermediate 277c Ethyl 4-({6-[(dimethylamino)carbonyl]-1-oxidopyridin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate

The title compound was synthesized in a similar fashion as described for Intermediate 252d, by reacting ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate and 5-bromo-N,N-dimethylpyridine-2-carboxamide 1-oxide. LC-MS (ESI, pos): 386.00.

Preparation of Intermediate 277d Ethyl 4-({6-[(dimethylamino)carbonyl]pyridin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate

To a stirred solution of ethyl 4-({6-[(dimethylamino)carbonyl]-1-oxidopyridin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (176 mg, 0.457 mmol) in 15 mL of acetic acid, was added powdered Fe while keeping the temperature at 70° C. for 2 hrs. LC-MS showed that the reaction was complete. The reaction was cooled to room temperature, and the insoluble material was filtered. The mother liquor was diluted with EtOAc, washed with NaHCO₃, brine, and dried over Na₂SO₄, and concentrated. The crude product was introduced into a silica gel column and eluted with MeOH/CHCl₃ (2/98 to 5/95) to provide the product (135 mg, 85% yield) as colorless oil. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.16 Hz, 3H) 2.47 (s, 3 H) 3.15 (d, 6 H) 4.39 (q, J=7.03 Hz, 2 H) 6.25 (s, 1 H) 7.30 (d, J=2.45 Hz, 1 H) 7.55-7.64 (m, 1 H) 7.64-7.76 (m, 1 H) 8.00 (s, 1 H) 8.38 (s, 1 H); LC-MS (ESI)+m/z=369.00 (M+H)⁺.

Example 278 N,N-Dimethyl-5-(2-methyl-6-((2-methyl-2H-1,2,3-triazol-4-yl)carbamoyl)-benzofuran-4-yloxy)picolinamide

The title compound was prepared in a similar manner as described for Example 277, from Intermediate 277d and 2-methyl-2H-1,2,3-triazol-4-amine. ¹H NMR (300 MHz, CHLOROFORM-d) δ 2.48 (s, 3H) 3.15 (d, J=7.16 Hz, 6 H) 4.12 (s, 3 H) 6.27 (s, 1 H) 7.31 (dd, J=8.67, 2.83 Hz, 1 H) 7.43 (s, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 7.83 (s, 1 H) 8.10 (s, 1 H) 8.37 (d, J=2.64 Hz, 1 H) 8.51 (s, 1 H). LCMS m/z 421.00 (M+H)⁺.

Example 279 5-(6-((5-Methoxypyrazin-2-yl)carbamoyl)-2-methylbenzofuran-4-yloxy)-N,N-dimethylpicolinamide

The title compound was prepared in a similar manner as described for Example 277, from Intermediate 277d and 5-methoxypyrazin-2-amine. ¹H NMR (300 MHz, CHLOROFORM-d) δ 2.48 (s, 3 H) 3.15 (d, 6 H) 3.99 (s, 3 H) 6.27 (s, 1 H) 7.28-7.38 (m, 1 H) 7.48 (s, 1 H) 7.61-7.76 (m, 1 H) 7.79-8.02 (m, 2 H) 8.30-8.47 (m, 2 H) 9.19 (s, 1 H). LCMS m/z 448.00 (M+H)⁺.

Example 280 N[5-(Dimethylamino)pyrazin-2-yl]-2-methyl-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1-benzofuran-6-carboxamide

To a solution of N²-N²-dimethylpyrizane-diamine (368 mg, 2.66 mmol) in DCE at 0° C. was added Al(CH₃)₂Cl (3.0 mL, 1.0M) drop wise. After the reaction was stirred at room temperature for 20 minutes, ethyl 2-methyl-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1-benzofuran-6-carboxylate (100 mg, 0.26 mmol) was added. The reaction was stirred at room temperature for 14 hours. The sample was diluted with CH₂Cl₂ and quenched with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL) slowly (caution). The organic layer was washed with brine and dried over Na₂SO₄ and concentrated. The crude sample was introduced into a silica gel column and eluted with (5-10% MeOH/CHCl₃) to provide the product (110 mg, 85% yield) as white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ 1.59 (s, 3 H) 2.48 (s, 3 H) 3.12 (s, 6 H) 6.22 (s, 1 H) 7.16 (d, J=8.67 Hz, 1 H) 7.58 (d, J=1.13 Hz, 1 H) 7.70 (d, J=1.32 Hz, 1 H) 7.92 (s, 1H) 8.23 (dd, J=8.57, 2.54 Hz, 2 H) 8.69 (d, J=2.45 Hz, 1 H) 9.15 (d, J=1.32 Hz, 1 H); MS (ESI, pos): 468.

Preparation of Intermediate 280a Ethyl 2-methyl-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1-benzofuran-6-carboxylate

A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (500 mg, 2.27mmol), 2-bromo-5-methanesulfonyl pyridine (590 mg, 2.57 mmol), Cs₂CO₃ (1.1 g , 4.12 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over Na₂SO₄ and concentrated. The product was purified via gradient silica gel chromatography on silica gel using EtOAc/Hex (10/90 to 30/70) to afford the title compound (830 mg, 88%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=7.16 Hz, 3 H) 2.48 (s, 3 H) 3.01-3.19 (m, 3 H) 4.41 (q, J=7.16 Hz, 2 H) 6.23 (d, J=0.94 Hz, 1 H) 7.02-7.18 (m, 2 H) 7.64 (d, J=1.13 Hz, 1 H) 7.85-7.96 (m, 1 H) 8.02-8.10 (m, 1 H); (ESI, pos): 376.

Examples 281-284 were prepared in a similar manner as described for Example 280, from Intermediate 280a and the appropriate amino heterocycles.

Example 281 2-Methyl-N-(5-methylpyridin-2-yl)-4-(5-(methylsulfonyl)pyridin-2-yloxy)-benzofuran-6-carboxamide

Example 282 2-Methyl-N-(2-methyl-2H-1,2,3-triazol-4-yl)-4-(5-(methylsulfonyl)pyridin-2-yloxy)benzofuran-6-carboxamide

Example 283 2-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-4-(5-(methylsulfonyl)-pyridin-2-yloxy)-benzofuran-6-carboxamide

Example 284 N-(5-Methoxypyrazin-2-yl)-2-methyl-4-(5-(methylsulfonyl)-pyridin-2-yloxy)-benzofuran-6-carboxamide

Example MW MF NMR m/z 281 437.5 C22H19N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.32 (s, 3 H) 438.00 2.48 (s, 3 H) 3.11 (s, 3 H) 6.23 (s, 1 H) 7.17 (d, J = 8.67 Hz, 1 H) 7.55-7.68 (m, 2 H) 7.95 (s, 1 H) 8.11 (s, 1 H) 8.19-8.40 (m, 2 H) 8.64 (d, 1 H) 8.69 (d, J = 2.45 Hz, 1 H) 282 427.4 C19H17N5O5S 1H NMR (300 MHz, DMSO-d6) d ppm 2.50 (s, 3 H) 3.33 (s, 3 H) 428.00 4.14 (s, 3 H) 6.50 (s, 1 H) 7.44 (d, J = 8.67 Hz, 1 H) 7.80 (s, 1 H) 8.02 (s, 1 H) 8.22 (s, 1 H) 8.42 (dd, J = 8.67, 2.64 Hz, 1 H) 8.66 (d, J = 2.45 Hz, 1 H) 11.35 (s, 1 H) 283 426.5 C20H18N4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.47 (s, 3 H) 427.00 3.11 (s, 3 H) 3.77 (s, 3 H) 6.22 (s, 1 H) 6.82 (d, J = 2.26 Hz, 1 H) 7.05-7.21 (m, 1 H) 7.28 (d, J = 2.26 Hz, 1 H) 7.55 (d, J = 1.13 Hz, 1 H) 7.89 (s, 1 H) 8.22 (dd, J = 8.67, 2.45 Hz, 1 H) 8.68 (d, J = 2.45 Hz, 1 H) 8.86 (s, 1 H) 284 454.5 C21H18N4O6S 1H NMR (300 MHz, DMSO-d6) d ppm 2.47 (s, 3 H) 3.32 (s, 3 H) 455.00 3.93 (s, 3 H) 6.47 (s, 1 H) 7.41 (d, J = 8.67 Hz, 1 H) 7.80 (s, 1 H) 8.20 (d, J = 7.16 Hz, 2 H) 8.39 (dd, J = 8.67, 2.64 Hz, 1 H) 8.63 (d, J = 2.45 Hz, 1 H) 8.94 (s, 1 H) 10.94 (s, 1 H)

Example 285 N2,N2-Dimethyl-N6-(5-methylpyridin-2-yl)-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-2,6-dicarboxamide

2-Amino-5-methyl pyridine (226 mg, 2.09 mmol) was dissolved in DCE (10 mL) at 0° C., and Al(CH₃)₂Cl (2.09 mL, 1M in hexanes) was then added drop-wise. After stirring the mixture at room temperature for 30 minutes, ethyl 2-(dimethylcarbamoyl)-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxylate (90 mg, 0.21 mmol) was then added and the stirring was continued for another 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl₃, washed with brine, and dried over MgSO₄. The product was purified by reverse phase HPLC to give the title compound (61 mg, 61%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.32 (s, 3 H) 3.08 (s, 3 H) 3.15 (s, 3 H) 3.34 (s, 3 H) 7.12-7.18 (m, 2 H) 7.19 (s, 1 H) 7.58 (dd, J=8.48, 2.26 Hz, 1 H) 7.87-7.98 (m, 2 H) 7.99 (s, 1 H) 8.11 (s, 1 H) 8.24 (d, J=8.48 Hz, 1 H) 8.64 (s, 1 H). LCMS m/z 494.0 (M+H)⁺.

Preparation of Intermediate 285a Ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxylate

To a solution of ethyl 2-methyl-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (252d) (226 mg, 0.604 mmol) and NBS (183 mg, 1.03 mmol) in CHCl₃ (10 mL) was added benzoyl peroxide (14.6 mg, 0.0604 mmol). After stirring the mixture at refluxed for 4 hr, the solvent was evaporated. The product was purified by gradient silica gel chromatography with hexanes/EtOAc (100/0 to 70/30) to give the title compound (200 mg, 73%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.39 (t, J=7.16 Hz, 3 H) 3.07 (s, 3 H) 4.39 (q, J=7.16 Hz, 2 H) 4.53 (s, 2 H) 6.62 (s, 1 H) 7.05-7.18 (m, 2 H) 7.62 (d, J=0.75 Hz, 1 H) 7.86-7.98 (m, 2 H) 8.07 (d, J=0.75 Hz, 1 H).

Preparation of Intermediate 285b Ethyl 2-formyl-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate

A solution of ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (320 mg, 0.706 mmol) and IBX (395 mg, 1.41 mmol) in DMSO (2 mL) was heated at 65° C. for 3 h. The reaction was quenched with water and the product was extracted with CHCl₃. The combined organic layers were washed with water (2×), dried over MgSO₄, and concentrated. The product was purified by gradient chromatography on silica gel using hexanes/EtOAc (100/0 to 40/60) to give the title compound (230 mg, 84%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.09 (s, 3H) 4.41 (q, J=7.16 Hz, 2 H) 7.14-7.23 (m, 2 H) 7.46 (d, J=0.94 Hz, 1 H) 7.62 (d, J=0.94 Hz, 1 H) 7.89-8.02 (m, 2 H) 8.15 (t, J=0.94 Hz, 1 H) 9.89 (s, 1 H).

Preparation of Intermediate 285c 6-(Ethoxycarbonyl)-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-2-carboxylic acid

To 10 mL of acetonitrile was added periodic acid (232 mg, 1.02 mmol), and the solution was stirred vigorously at room temperature for 15 min. Ethyl 2-formyl-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxylate (360 mg, 0.927 mmol) was then added at 0° C. followed by the addition of pyridium fluorochromate (3.69 mg, 0.0185 mmol) in CH₃CN (1 mL). The reaction was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to give the title compound (355 mg, 95%) as an orange solid. The crude product was used in the next step without further purification. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.09 (s, 3 H) 4.41 (q, J=7.16 Hz, 2 H) 7.12-7.22 (m, 2 H) 7.55 (d, J=1.13 Hz, 1 H) 7.63 (d, J=1.13 Hz, 1 H) 7.92-8.02 (m, 2 H) 8.17 (s, 1 H).

Preparation of Intermediate 285d Ethyl 2-(dimethylcarbamoyl)-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxylate

To a solution of 6-(ethoxycarbonyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-2-carboxylic acid (450 mg, 1.11 mmol) in DMF (10 mL) was added HATU (846 mg, 2.23 mmol), DIEA (719 mg, 5.56 mmol) and the solution was stirred at 0° C. for 15 min. Dimethylamine hydrochloride (136 mg, 1.67 mmol) was added and the solution was warmed gradually to room temperature and stirred for 14 h. Water was added and the product was extracted with CHCl₃. The combined organic layers were washed with water (2×), brine, dried over Na₂SO₄, and concentrated. The product was purified by gradient silica gel chromatography using CHCl₃/MeOH (100/0 to 95/5) to give the title compound (460 mg, 96%) as a light yellow solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.07 (s, 3 H) 3.13 (s, 3 H) 3.33 (s, 3 H) 4.40 (q, J=7.16 Hz, 2 H) 7.07-7.15 (m, 2 H) 7.16 (d, J=0.75 Hz, 1 H) 7.65 (d, J=0.94 Hz, 1 H) 7.87-7.94 (m, 2H) 8.10-8.15 (d, J=0.94 Hz, 1 H).

Examples 286-292 were prepared in a similar manner as described for Example 285, from Intermediate 285d or ethyl 2-(azetidine-1-carbonyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate, which was prepared in a similar manner as described for Intermediate 285d, from Intermediate 285c and azetidine hydrochloride.

Example 286 N2,N2-Dimethyl-N6-(1-methyl-1H-pyrazol-3-yl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-2,6-dicarboxamide

Example 287 N6-(5-Methoxypyrazin-2-yl)-N2,N2-dimethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-2,6-dicarboxamide

Example 288 N2,N2-Dimethyl-4-[4-(methylsulfonyl)phenoxy]-N6-(2-methyl-2H-1,2,3-triazol-4-yl)-1-benzofuran-2,6-dicarboxamide

Example 289 N6-(4-Methoxypyridin-2-yl)-N2,N2-dimethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-2,6-dicarboxamide

Example 290 2-(Azetidin-1-ylcarbonyl)-N-(5-methylpyridin-2-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

Example 291 2-(Azetidin-1-ylcarbonyl)-N-(1-methyl-1H-pyrazol-3-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

Example 292 2-(Azetidin-1-ylcarbonyl)-4-[4-(methylsulfonyl)phenoxy]-N-(2-methyl-2H-1,2,3-triazol-4-yl)-1-benzofuran-6-carboxamide

Example MW MF NMR m/z 286 482.5 C23H22N4O6S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 3.08 (s, 3 H) 483.00 3.14 (s, 3 H) 3.33 (s, 3 H) 3.79 (s, 3 H) 6.79 (d, J = 2.26 Hz, 1 H) 7.11-7.20 (m, 3 H) 7.29 (d, J = 2.26 Hz, 1 H) 7.45 (d, J = 1.13 Hz, 1 H) 7.88-8.05 (m, 3 H) 8.58 (s, 1 H) 287 510.5 C24H22N4O7S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 3.08 (s, 3 H) 511.00 3.15 (s, 3 H) 3.34 (s, 3 H) 3.98 (s, 3 H) 7.16 (d, J = 8.67 Hz, 2 H) 7.19 (s, 1 H) 7.52 (s, 1 H) 7.88-7.97 (m, 3 H) 7.98 (s, 1 H) 8.40 (s, 1 H) 9.16 (s, 1 H) 288 483.5 C22H21N5O6S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 3.08 (s, 3 H) 484.00 3.15 (s, 3 H) 3.33 (s, 3 H) 4.11 (s, 3 H) 7.10-7.21 (m, 3 H) 7.48 (d, J = 1.13 Hz, 1 H) 7.88-7.99 (m, 3 H) 8.09 (s, 1 H) 8.64 (s, 1 H) 289 509.5 C25H23N3O7S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 3.08 (s, 3 H) 510.00 3.15 (s, 3 H) 3.34 (s, 3 H) 3.90 (s, 3 H) 6.64 (dd, J = 5.84, 2.26 Hz, 1 H) 7.17 (d, J = 8.67 Hz, 2 H) 7.20 (s, 1 H) 7.53 (s, 1 H) 7.93 (d, J = 8.67 Hz, 2 H) 7.97-8.03 (m, 2 H) 8.05 (d, J = 5.84 Hz, 1 H) 9.02 (s, 1H) 290 505.6 C26H23N3O6S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 2.32 (s, 3 H) 506.00 2.39-2.56 (m, 2 H) 3.08 (s, 3 H) 4.26 (t, J = 7.82 Hz, 2 H) 4.69 (t, J = 7.82 Hz, 2 H) 7.09-7.19 (m, 2 H) 7.28 (s, 1 H) 7.51 (d, J = 1.13 Hz, 1 H) 7.58 (dd, J = 8.29, 1.98 Hz, 1 H) 7.88-7.96 (m, 2 H) 7.97 (s, 1 H) 8.12 (s, 1 H) 8.23 (d, J = 8.29 Hz, 1 H) 8.49 (s, 1 H) 291 494.5 C24H22N4O6S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 2.38-2.53 (m, 2 495.00 H) 3.09 (s, 3 H) 3.81 (s, 3 H) 4.25 (t, J = 7.82 Hz, 2 H) 4.68 (t, J = 7.63 Hz, 2 H) 6.79 (d, J = 2.26 Hz, 1 H) 7.10-7.20 (m, 2 H) 7.27 (s, 1 H) 7.30 (d, J = 2.26 Hz, 1 H) 7.45 (d, J = 1.13 Hz, 1 H) 7.84-8.04 (m, 3 H) 8.50 (s, 1 H) 292 495.5 C23H21N5O6S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 2.37-2.55 (m, 2 496.00 H) 3.09 (s, 3 H) 4.12 (s, 3 H) 4.26 (t, J = 7.72 Hz, 2 H) 4.69 (t, J = 7.63 Hz, 2 H) 7.11-7.19 (m, 2 H) 7.27 (s, 1 H) 7.47 (d, J = 0.94 Hz, 1 H) 7.86-8.00 (m, 3 H) 8.10 (s, 1 H) 8.54 (s, 1 H)

Example 293 4-{4-[(Dimethylamino)sulfonyl]-3-fluorophenoxy}-N-(4-methoxypyridin-2-yl)-2-methyl-1-benzofuran-6-carboxamide

To a solution of 4-methoxypyridin-2-amine (295 mg, 2.37 mmol) in DCE at 0° C. was added Al(CH₃)₂Cl (3.0 mL, 1.0M) drop wise, and the reaction was stirred for 20 minutes at room temperature. Ethyl 4-{4-[(dimethylamino)sulfonyl]-3-fluorophenoxy}-2-methyl-1-benzofuran-6-carboxylate (100 mg, 0.24 mmol) was then added and the reaction was stirred at room temperature for an additional 14 hours. The sample was diluted with CH₂Cl₂ and quenched with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL). The organic layer was washed with brine and dried over Na₂SO₄ and concentrated under reduced pressure. The crude sample was introduced into a silica gel column and eluted with MeOH/CHCl₃ (5/95-10/90) to provide the product (110 mg, 93% yield) as white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.49 (s, 3 H) 2.84 (d, J=1.51 Hz, 6 H) 3.91 (s, 3 H) 6.26 (s, 1 H) 6.64 (dd, J=5.75, 2.35 Hz, 1 H) 6.71-6.91 (m, 2 H) 7.52 (s, 1 H) 7.81 (t, J=8.29 Hz, 1 H) 7.91 (s, 1 H) 8.01 (s, 1 H) 8.09 (d, J=5.84 Hz, 1 H) 8.59 (s, 1 H); MS (ESI, pos): 500.

Preparation of Intermediate 293a Ethyl 4-{4-[(dimethylamino)sulfonyl]-3-fluorophenoxy}-2-methyl-1-benzofuran-6-carboxylate

A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (500 mg, 2.27mmol), 2,4-difluoro-N,N-dimethylbenzenesulfonamide (553 mg, 2.75 mmol), Cs₂CO₃ (1.1 g, 4.12 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na₂SO₄ and concentrated. The product was purified via gradient silica gel column chromatography using EtOAc/Hex (10/90 to 30/70) to afford the desired compound (850 mg, 91%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.16 Hz, 3 H) 2.48 (s, 3 H) 2.78-2.94 (m, 6 H) 4.40 (q, J=7.10 Hz, 2 H) 6.24 (s, 1 H) 6.66-6.94 (m, 2 H) 7.65 (s, 1 H) 7.79 (t, J=8.38 Hz, 1 H) 8.04 (s, 1 H); MS (ESI, pos): 422.

Examples 294-308 were prepared in a similar manner as described for Example 293, from Intermediate 293a, or ethyl 4-(4-(azetidin-1-ylsulfonyl)phenoxy)-2-methylbenzofuran-6-carboxylate, which was prepared in a similar manner as described for Intermediate 293a, from ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate and 1-(4-fluorophenylsulfonyl)azetidine.

Example 294 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzofuran-6-carboxamide

Example 295 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-N-(4-methoxypyridin-2-yl)-2-methyl-benzofuran-6-carboxamide

Example 296 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-2-methyl-N-(pyridin-2-yl)benzofuran-6-carboxamide

Example 297 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-2-methyl-N-(5-methylpyridin-2-yl)-benzofuran-6-carboxamide

Example 298 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-2-methyl-N-(2-methyl-2H-1,2,3-triazol-4-yl)benzofuran-6-carboxamide

Example 299 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-N-(5-(dimethylamino)-pyrazin-2-yl)-2-methylbenzofuran-6-carboxamide

Example 300 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-N-(5-chloropyridin-2-yl)-2-methyl-benzofuran-6-carboxamide

Example 301 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-N-(5-(hydroxymethyl)-pyridin-2-yl)-2-methylbenzofuran-6-carboxamide

Example 302 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-N-(5-ethoxypyridin-2-yl)-2-methyl-benzofuran-6-carboxamide

Example 303 4-(4-(Azetidin-1-ylsulfonyl)phenoxy)-N-(5-methoxypyrazin-2-yl)-2-methyl-benzofuran-6-carboxamide

Example 304 4-{4-[(Dimethylamino)sulfonyl]-3-fluorophenoxy}-2-methyl-N-(5-methyl-pyridin-2-yl)-1-benzofuran-6-carboxamide

Example 305 4-{4-[(Dimethylamino)sulfonyl]-3-fluorophenoxy}-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)-1-benzofuran-6-carboxamide

Example 306 4-{4-[(Dimethylamino)sulfonyl]-3-fluorophenoxy}-2-methyl-N-(2-methyl-2H-1,2,3-triazol-4-yl)-1-benzofuran-6-carboxamide

Example 307 4-{4-[(Dimethylamino)sulfonyl]-3-fluorophenoxy}-N-(5-methoxypyrazin-2-yl)-2-methyl-1-benzofuran-6-carboxamide

Example 308 N-[5-(Dimethylamino)pyrazin-2-yl]-4-{4-[(dimethylamino)-sulfonyl]-3-fluorophenoxy}-2-methyl-1-benzofuran-6-carboxamide

Example MW MF NMR m/z 294 466.5 C23H22N4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.02-2.25 (m, 2 467.20 H) 2.48 (s, 3 H) 3.71-3.93 (m, 7 H) 6.25 (d, J = 0.75 Hz, 1 H) 6.82 (d, J = 2.26 Hz, 1 H) 7.06-7.17 (m, 2 H) 7.30 (d, J = 2.26 Hz, 1 H) 7.48 (d, J = 1.13 Hz, 1 H) 7.75-7.92 (m, 3 H) 8.62 (s, 1 H) 295 493.5 C25H23N3O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.00-2.29 (m, 2 494.00 H) 2.50 (s, 3 H) 3.82 (t, J = 7.54 Hz, 4 H) 3.92 (s, 3 H) 6.27 (s, 1 H) 6.64 (dd, J = 5.84, 2.45 Hz, 1 H) 7.06-7.20 (m, 2 H) 7.52 (d, J = 1.13 Hz, 1 H) 7.78-7.87 (m, 2 H) 7.90 (s, 1 H) 8.02 (d, J = 2.26 Hz, 1 H) 8.09 (d, J = 5.84 Hz, 1 H) 8.63 (s, 1 H) 296 463.5 C24H21N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.03-2.22 (m, 2 464.00 H) 2.49 (s, 3 H) 3.81 (t, J = 7.63 Hz, 4 H) 6.26 (s, 1 H) 7.05-7.18 (m, 3 H) 7.53 (d, J = 1.13 Hz, 1 H) 7.72-7.87 (m, 3 H) 7.90 (s, 1 H) 8.37 (d, J = 8.29 Hz, 2 H) 8.57 (s, 1 H) 297 477.5 C25H23N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.03-2.21 (m, 2 478.00 H) 2.32 (s, 3 H) 2.44-2.58 (m, 3 H) 3.80 (t, J = 7.54 Hz, 4 H) 6.25 (s, 1 H) 7.05-7.20 (m, 2 H) 7.52 (d, J = 1.13 Hz, 1 H) 7.58 (dd, J = 8.67, 2.07 Hz, 1 H) 7.76-7.87 (m, 2 H) 7.90 (s, 1 H) 8.12 (s, 1 H) 8.26 (d, J = 8.48 Hz, 1 H) 8.57 (s, 1 H) 298 467.5 C22H21N5O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.05-2.28 (m, 2 468.20 H) 2.50 (s, 3 H) 3.75-3.99 (m, 4 H) 4.14 (s, 3 H) 6.23-6.38 (m, 1 H) 7.06-7.24 (m, 2 H) 7.47-7.62 (m, 1 H) 7.78-7.99 (m, 3 H) 8.13 (s, 1 H) 8.43 (s, 1 H) 299 507.6 C25H25N5O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.01-2.22 (m, 2 508.00 H) 2.48 (s, 3 H) 3.13 (s, 6 H) 3.80 (t, J = 7.63 Hz, 4 H) 6.25 (s, 1 H) 7.06-7.18 (m, 2 H) 7.52 (d, J = 1.13 Hz, 1 H) 7.71 (d, J = 1.13 Hz, 1 H) 7.76-7.85 (m, 2 H) 7.87 (s, 1 H) 8.22 (s, 1 H) 9.14 (d, J = 1.32 Hz, 1 H) 300 498 C24H20ClN3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.06-2.23 (m, 2 498.20 H) 2.49 (s, 3 H) 3.81 (t, J = 7.63 Hz, 4 H) 6.26 (d, J = 0.75 Hz, 1 H) 7.07-7.20 (m, 2 H) 7.52 (d, J = 1.32 Hz, 1 H) 7.73 (dd, J = 8.95, 2.54 Hz, 1 H) 7.78-7.88 (m, 2 H) 7.89 (s, 1 H) 8.26 (d, J = 2.45 Hz, 1 H) 8.37 (d, J = 9.04 Hz, 1 H) 8.63 (s, 1 H) 301 493.5 C25H23N3O6S 1HNMR: HB110684-1121H NMR (300 MHz, CHLOROFORM- 494.20 d) d ppm 1.98-2.25 (m, 2 H) 2.49 (s, 3 H) 3.80 (t, J = 7.63 Hz, 4 H) 4.72 (s, 2 H) 6.26 (d, J = 0.75 Hz, 1 H) 7.04-7.19 (m, 2 H) 7.53 (s, 1 H) 7.75-7.88 (m, 3 H) 7.91 (s, 1 H) 8.23-8.47 (m, 2 H) 8.67 (s, 1 H) 302 507.6 C26H25N3O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm −0.12 (t, J = 6.97 Hz, 508.20 3 H) 0.46-0.67 (m, 2 H) 0.92 (s, 3 H) 2.24 (t, J = 7.63 Hz, 4 H) 2.52 (q, J = 6.97 Hz, 2 H) 4.69 (s, 1 H) 5.51-5.63 (m, 2 H) 5.74-5.81 (m, 1 H) 5.95 (d, J = 1.13 Hz, 1 H) 6.25 (d, J = 8.85 Hz, 2 H) 6.30-6.37 (m, 1 H) 6.39-6.48 (m, 1 H) 6.72 (s, 1 H) 6.84-6.97 (m, 1 H) 303 494.5 C24H22N4O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.01-2.27 (m, 2 495.20 H) 2.49 (s, 3 H) 3.81 (t, J = 7.63 Hz, 4 H) 3.99 (s, 3 H) 6.26 (s, 1 H) 7.06-7.20 (m, 2 H) 7.52 (d, J = 1.32 Hz, 1 H) 7.75-7.87 (m, 2 H) 7.88 (s, 1 H) 7.95 (d, J = 1.32 Hz, 1 H) 8.33 (s, 1 H) 9.19 (d, J = 1.32 Hz, 1 H) 304 483.5 C24H22FN3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.32 (s, 3 H) 484.00 2.49 (s, 3 H) 2.84 (d, J = 1.88 Hz, 6 H) 6.26 (d, J = 0.94 Hz, 1 H) 6.69-6.96 (m, 2 H) 7.53 (d, J = 1.32 Hz, 1 H) 7.59 (dd, J = 8.38, 2.17 Hz, 1 H) 7.74-7.87 (m, 1 H) 7.91 (s, 1 H) 8.13 (s, 1 H) 8.26 (d, J = 8.48 Hz, 1 H) 8.54 (s, 1 H) 305 472.5 C22H21FN4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.48 (s, 3 H) 473.00 2.84 (d, J = 1.88 Hz, 6 H) 3.77-3.92 (m, 3 H) 6.25 (s, 1 H) 6.69-6.94 (m, 3 H) 7.30 (d, J = 2.07 Hz, 1 H) 7.45-7.56 (m, 1 H) 7.73-7.93 (m, 2 H) 8.58 (s, 1 H) 306 473.5 C21H20FN5O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.50 (s, 3 H) 474.00 2.84 (d, J = 1.70 Hz, 6 H) 4.13 (s, 3 H) 6.26 (d, J = 0.75 Hz, 1 H) 6.70-6.95 (m, 2 H) 7.49 (d, J = 1.32 Hz, 1 H) 7.81 (t, J = 8.38 Hz, 1 H) 7.87 (s, 1 H) 8.12 (s, 1 H) 8.47 (s, 1 H) 307 500.5 C23H21FN4O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.50 (s, 3 H) 501.00 2.84 (d, J = 1.70 Hz, 6 H) 3.99 (s, 3 H) 6.26 (s, 1 H) 6.70-6.97 (m, 2 H) 7.53 (s, 1 H) 7.81 (t, J = 8.29 Hz, 1 H) 7.91 (s, 1 H) 7.95 (d, J = 1.13 Hz, 1 H) 8.35 (s, 1 H) 9.19 (d, J = 1.13 Hz, 1 H) 308 513.6 C24H24FN5O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.49 (s, 3 H) 514.00 2.84 (d, J = 1.70 Hz, 6 H) 3.13 (s, 6 H) 6.26 (s, 1 H) 6.69-6.92 (m, 2 H) 7.53 (s, 1 H) 7.70 (d, J = 1.32 Hz, 1 H) 7.80 (t, J = 8.29 Hz, 1 H) 7.90 (s, 1 H) 8.28 (s, 1 H) 9.15 (s, 1 H)

Example 309 2-(Methoxymethyl)-N-(5-methylpyridin-2-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

To a solution of 2-(methoxymethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylic acid (130 mg, 0.345 mmol) in DMF (5 mL) was added HATU (263 mg, 0.691 mmol) and DIEA (89.3 mg, 0.691 mmol). After stirring the solution at 0° C. for 15 minutes, 2-amino-5-methyl pyridine (74.7 mg, 0.691 mmol) was added. The solution was warmed gradually to room temperature and stirred for 14 h. The reaction was concentrated under high vacuum, and the product was purified by reverse phase HPLC to give the title compound (88 mg, 55%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.36 (s, 3 H) 3.07 (s, 3 H) 3.46 (s, 3 H) 4.56 (s, 2 H) 6.59 (s, 1 H) 7.07-7.18 (m, 2 H) 7.53 (d, J=1.32 Hz, 1 H) 7.74 (dd, J=8.67, 1.32 Hz, 1 H) 7.85-7.95 (m, 2 H) 8.00 (s, 1 H) 8.09 (s, 1 H) 8.22 (d, J=8.67 Hz, 1 H) 9.10 (s, 1 H). LCMS m/z 467.20 (M+H)⁺.

Preparation of Intermediate 309a 2-(Methoxymethyl)-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxylic acid

To a solution of ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285a) (750 mg, 1.65 mmol) in THF and MeOH (3:1, 15 mL) was added NaOMe in MeOH(25% w/w, 1 mL) drop-wise at 0° C. After the solution was stirred at 0° C. for 2 hours, water was added and the stirring was continued for 14 h. The solvents were reduced under reduced pressure. To the aqueous solution was added 1N HCl until the pH ˜1. The product was extracted with CHCl₃ and dried over MgSO₄. The solution was concentrated to give the title compound (610 mg, 98%) as a white solid. The product was usedin the next step without further purification. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 3.07 (s, 3 H) 3.46 (s, 3 H) 4.56 (s, 2 H) 6.58 (s, 1 H) 7.07-7.17 (m, 2 H) 7.67 (d, J=1.13 Hz, 1 H) 7.85-7.99 (m, 2 H) 8.13 (d, J=1.13 Hz, 1 H).

Examples 310-315 were prepared in a similar manner as described for Example 309, from Intermediate 309a and the appropriate amino heterocycles.

Example 310 2-(Methoxymethyl)-N-(1-methyl-1H-pyrazol-3-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

Example 311 N-[5-(Dimethylamino)pyrazin-2-yl]-2-(methoxymethyl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

Example 312 2-(Methoxymethyl)-N-(5-methoxypyrazin-2-yl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxamide

Example 313 2-(Methoxymethyl)-4-[4-(methylsulfonyl)phenoxy]-N-(2-methyl-2H-1,2,3-triazol-4-yl)-1-benzofuran-6-carboxamide

Example 314 2-(Methoxymethyl)-N-(4-methoxypyridin-2-yl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxamide

Example 315 2-(Methoxymethyl)-N-(5-methylisoxazol-3-yl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxamide

Example MW MF NMR m/z 310 455.5 C22H21N3O6S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 456.00 3.07 (s, 3 H) 3.45 (s, 3 H) 3.80 (s, 3 H) 4.55 (s, 2 H) 6.58 (s, 1 H) 6.81 (d, J = 2.26 Hz, 1 H) 7.07-7.19 (m, 2 H) 7.29 (d, J = 2.26 Hz, 1 H) 7.47 (d, J = 1.13 Hz, 1 H) 7.84-8.00 (m, 3 H) 8.78 (s, 1 H) 311 496.5 C24H24N4O6S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 497.00 3.06 (s, 3 H) 3.11 (s, 6 H) 3.45 (s, 3 H) 4.54 (s, 2 H) 6.57 (s, 1 H) 7.04-7.19 (m, 2 H) 7.51 (d, J = 1.13 Hz, 1 H) 7.67 (d, J = 1.51 Hz, 1 H) 7.83-8.06 (m, 3 H) 8.43 (s, 1 H) 9.12 (d, J = 1.51 Hz, 1 H) 312 483.5 C23H21N3O7S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 484.00 3.07 (s, 3 H) 3.46 (s, 3 H) 3.99 (s, 3 H) 4.56 (s, 2 H) 6.58 (s, 1 H) 7.10-7.20 (m, 2 H) 7.53 (d, J = 1.13 Hz, 1 H) 7.90-8.00 (m, 4 H) 8.66 (s, 1 H) 9.21 (d, J = 1.32 Hz, 1 H) 313 456.5 C21H20N4O6S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 457.00 3.07 (s, 3 H) 3.45 (s, 3 H) 4.12 (s, 3 H) 4.55 (s, 2 H) 6.58 (s, 1 H) 7.08-7.20 (m, 2 H) 7.46 (d, J = 1.13 Hz, 1 H) 7.83-8.01 (m, 3 H) 8.10 (s, 1 H) 8.48 (s, 1 H) 314 482.5 C24H22N2O7S 1H NMR (300 MHz, DMSO-D6) d ppm 3.21 (s, 3 483.20 H) 3.31 (s, 3 H) 3.86 (s, 3 H) 4.56 (s, 2 H) 6.78-6.86 (m, 2 H) 7.27 (d, J = 8.67 Hz, 2 H) 7.69 (s, 1 H) 7.77 (d, J = 1.70 Hz, 1 H) 7.94 (d, J = 8.67 Hz, 2 H) 8.21 (d, J = 5.65 Hz, 1 H) 8.26 (s, 1 H) 10.98 (s, 1 H) 315 456.5 C22H20N2O7S 1H NMR (300 MHz, CHLOROFORM-D) d ppm 457.00 2.43 (s, 3 H) 3.08 (s, 3 H) 3.46 (s, 3 H) 4.56 (s, 2 H) 6.58 (s, 1 H) 6.82 (s, 1 H) 7.10-7.18 (m, 2 H) 7.46 (d, J = 1.32 Hz, 1 H) 7.88-7.99 (m, 3 H) 8.69 (s, 1 H)

Example 316 2-(Hydroxymethyl)-N-(5-methylpyridin-2-yl)-4-(4-(methylsulfonyl)-phenoxy)benzofuran-6-carboxamide

To a solution of 2-amino-5-methyl pyridine (305 mg, 2.82 mmol) in DCE (10 mL) at 0° C. was added dimethylaluminum chloride (1M in hexanes, 2.82 mL) drop-wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-(hydroxymethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (110 mg, 0.282 mmol) was then added, and the stirring was continued for another 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl₃, washed with brine and dried over MgSO₄. The product was purified by reverse phase HPLC to give the title compound (90 mg, 71%) as a white solid. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3 H) 3.20 (s, 3 H) 4.58 (d, J=5.84 Hz, 2 H) 5.60 (t, J=5.84 Hz, 1 H) 6.61 (s, 1 H) 7.24 (d, J=8.67 Hz, 2 H) 7.66 (dd, J=8.48 , 2.26 Hz, 1 H) 7.70 (s, 1 H) 7.93 (d, J=8.67 Hz, 2 H) 8.06 (d, J=8.48 Hz, 1 H) 8.22 (d, J=2.26 Hz, 1 H) 8.24 (s, 1 H) 10.83 (s, 1 H). LCMS m/z 453.0 (M+H)⁺.

Preparation of Intermediate 316a Ethyl 2-(hydroxymethyl)-4-(4-(methylsulfonyl)-phenoxy)-benzofuran-6-carboxylate

To a solution of ethyl 2-formyl-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285b) (230 mg, 0.592 mmol) in MeOH (10 mL) was added NaBH₄ (50 mg, 1.3 mmol). The mixture was stirred for half an hour. The solvent was evaporated, and the product was purified by gradient silica gel chromatography using CHCl₃/MeOH (100/0 to 98/2). The desired compound was isolated as a white solid (170 mg, 74%).

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 1.99 (t, J=6.22 Hz, 1 H) 3.06 (s, 3 H) 4.39 (q, J=7.16 Hz, 2 H) 4.78 (d, J=6.22 Hz, 2 H) 6.52 (d, J=1.13 Hz, 1 H) 7.00-7.17 (m, 2 H) 7.64 (d, J=1.13 Hz, 1 H) 7.87-7.97 (m, 2 H) 8.06 (s, 1 H).

Example 317 2-(Hydroxymethyl)-N-(1-methyl-1H-pyrazol-3-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

The title compound was prepared in a similar manner as described for Example 316, from Intermediate 316a and 1-methyl-1H-pyrazol-3-amine. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 3.07 (s, 3 H) 3.83 (s, 3 H) 4.78 (s, 2 H) 6.55 (s, 1 H) 6.84 (d, J=2.26 Hz, 1 H) 7.05-7.18 (m, 2 H) 7.31 (d, J=2.26 Hz, 1 H) 7.48 (d, J=1.13 Hz, 1 H) 7.79-8.06 (m, 3 H) 8.98 (s, 1 H); LCMS m/z 442.00 (M+H)⁺.

Example 318 N-(1-Methyl-1H-pyrazol-3-yl)-4-[4-(methylsulfonyl)phenoxy]-2-[(2-oxopyrrolidin-1-yl)methyl]-1-benzofuran-6-carboxamide

To a solution of 3-amino-1-methyl pyrazole (106 mg, 1.09 mmol) in DCE (10 mL) at 0° C. was added Al(CH₃)₂Cl (1.09 mL, 1M in hexanes) drop-wise. After removal of the ice-bath, the mixture was stirred for min at room temperature. Ethyl 4-(4-(methylsulfonyl)phenoxy)-2-((2-oxopyrrolidin-1-yl)methyl)benzofuran-6-carboxylate (50 mg, 0.11 mmol) was added and the stirring was continued for another 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl₃, washed with brine and dried over MgSO₄. The product was purified by reverse phase HPLC to give the title compound (22 mg, 47%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.97-2.13 (m, 2 H) 2.44 (t, J=8.01 Hz, 2 H) 3.08 (s, 3 H) 3.46 (t, J=6.97 Hz, 2 H) 3.81 (s, 3 H) 4.60 (s, 2 H) 6.54 (s, 1 H) 6.79 (d, J=2.26 Hz, 1 H) 7.09-7.17 (m, 2 H) 7.29 (d, J=2.26 Hz, 1 H) 7.44 (s, 1 H) 7.81-7.98 (m, 3 H) 8.54 (s, 1 H). LCMS m/z 509.0 (M+H)⁺.

Preparation of Intermediate 318a Ethyl 4-(4-(methylsulfonyl)phenoxy)-2-((2-oxopyrrolidin-1-yl)methyl)benzofuran-6-carboxylate

To a solution of 2-ketopyrrolidine (75.1 mg, 0.882 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 44 mg, 1.1 mmol) at room temperature. After stirring the reaction for 30 min, ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285a) (200 mg, 0.441 mmol) was added. The mixture was stirred at room temperature for another 2 h. Water was added to the reaction, and the product was extracted with CHCl₃. The combined organic layer was dried and concentrated. The product was purified by gradient silica gel chromatography using CHCl₃/MeOH (100/0 to 95/5) to give the title compound (50 mg, 25%) as a yellow oil. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 1.98-2.14 (m, 2 H) 2.42 (t, J=8.10 Hz, 2 H) 3.06 (s, 3 H) 3.44 (t, J=7.06 Hz, 2 H) 4.38 (q, J=7.16 Hz, 2 H) 4.58 (s, 2 H) 6.49 (d, J=0.75 Hz, 1 H) 7.04-7.12 (m, 2 H) 7.61 (d, J=1.13 Hz, 1 H) 7.83-7.94 (m, 2 H) 8.05 (t, J=1.13 Hz, 1 H).

Examples 319 and 320 were prepared in a similar manner as described for Example 318, from the corresponding ether ester intermediates, which were prepared in a similar manner as described for Intermediate 318a, starting from Intermediate 285a and dimethylamine or 2-methyl-1H-imidazole, respectively.

Example 319 2-[(Dimethylamino)methyl]-N-(5-methylpyridin-2-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.30 (s, 3 H) 2.32 (s, 6 H) 3.06 (s, 3 H) 3.61 (s, 2 H) 6.48 (s, 1 H) 7.07-7.18 (m, 2 H) 7.50 (d, J=1.13 Hz, 1 H) 7.57 (dd, J=8.48, 2.26 Hz, 1 H) 7.85-7.93 (m, 2 H) 7.94 (s, 1 H) 8.08 (s, 1 H) 8.25 (d, J=8.48 Hz, 1 H) 8.76 (s, 1 H); LCMS m/z 480.20 (M+H)⁺.

Example 320 2-[(2-Methyl-1H-imidazol-1-yl)methyl]-N-(5-methylpyridin-2-yl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.31 (s, 3 H) 2.46 (s, 3 H) 3.07 (s, 3 H) 5.16 (s, 2 H) 6.45 (s, 1 H) 6.91-6.94 (m, 1 H) 6.95 (d, J=1.32 Hz, 1 H) 7.08-7.19 (m, 2 H) 7.49 (d, J=1.32 Hz, 1 H) 7.58 (dd, J=8.67, 2.26 Hz, 1 H) 7.87-8.01 (m, 3 H) 8.10 (s, 1 H) 8.23 (d, J=8.48 Hz, 1 H) 8.67 (s, 1 H); LCMS m/z 517.00 (M+H)⁺.

Example 321 2-(Difluoromethyl)-N-(5-methylpyridin-2-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

2-Amino-5-methyl pyridine (264 mg, 2.44 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH₃)₂Cl (2.44 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-(difluoromethyl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (100 mg, 0.244 mmol) was added, and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl₃, washed with brine and dried over MgSO₄. The product was purified by reverse phase HPLC to give the title compound (92 mg, 80%) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.31 (s, 3 H) 3.08 (s, 3 H) 6.75 (t, J=53.94 Hz, 1 H) 6.98 (s, 1 H) 7.12-7.20 (m, 2 H) 7.51 (d, J=1.01 Hz, 1 H) 7.58 (dd, J=8.46, 2.15 Hz, 1 H) 7.91-7.96 (m, 2 H) 7.97 (s, 1 H) 8.11 (d, J=2.15 Hz, 1 H) 8.23 (d, J=8.46 Hz, 1 H) 8.54 (s, 1 H). LCMS m/z 473.0 (M+H)⁺.

Preparation of Intermediate 321a Ethyl 2-(difluoromethyl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate

To a solution of ethyl 2-formyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (285b) (500 mg 1.14 mmol) in CH₂Cl₂ (15 mL) was added DAST (238 mg, 1.48 mmol) at room temperature. The mixture was stirred for 1 hour and water was added. The product was extracted with CHCl₃, dried over MgSO₄ and concentrated. The residue was passed through a silica gel column eluting with hexanes/EtOAc (100/0 to 70/30) to give the title compound (400 mg, 86%) as a colorless oil. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.07 (s, 3 H) 4.40 (q, J=7.16 Hz, 2 H) 6.74 (t, J=53.78 Hz, 1 H) 6.95 (s, 1 H) 7.09-7.19 (m, 2 H) 7.65 (d, J=1.13 Hz, 1 H) 7.87-8.13 (s, 1 H).

Example 322 2-(Difluoromethyl)-N-(1-methyl-1H-pyrazol-3-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-6-carboxamide

The title compound was prepared in a similar manner as described for Example 321, from Intermediate 321a and 1-methyl-1H-pyrazol-3-amine. ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.06 (s, 3 H) 3.79 (s, 3 H) 6.73 (t, J=53.81 Hz, 1 H) 6.77 (d, J=2.27 Hz, 1 H) 6.95 (s, 1 H) 7.11-7.19 (m, 2 H) 7.28 (d, J=2.27 Hz, 1 H) 7.52 (d, J=1.26 Hz, 1 H) 7.87-7.95 (m, 2 H) 7.99 (s, 1 H); LCMS m/z 462.0 (M+H)⁺.

Example 323 4-[4-(Difluoromethyl)phenoxy]-N²,N²-dimethyl-N⁶-(5-methylpyridin-2-yl)-1-benzofuran-2,6-dicarboxamide

To a solution of 4-(4-formylphenoxy)-N²,N²-dimethyl-N⁶-(5-methylpyridin-2-yl)-1-benzofuran-2,6-dicarboxamide (40 mg, 0.09 mmol) in CH₂Cl₂ (5 mL) was added DAST (18.9 mg, 0.117 mmol) at room temperature. The mixture was stirred for 1 hour and water was added. The product was extracted with CHCl₃ three times, dried over MgSO₄, and concentrated. The product was purified by reverse phase HPLC to give the title compound (9 mg, 20%) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.31 (s, 3 H) 3.14 (s, 3 H) 3.33 (s, 3 H) 6.64 (t, J=56.59 Hz, 1 H) 7.12 (d, J=8.59 Hz, 2 H) 7.19 (s, 1 H) 7.39 (d, J=1.26 Hz, 1 H) 7.52 (d, J=8.59 Hz, 2 H) 7.58 (dd, J=8.46, 2.15 Hz, 1 H) 7.91 (s, 1 H) 8.10 (d, J=2.15 Hz, 1 H) 8.23 (d, J=8.46 Hz, 1 H) 8.60 (s, 1 H). LCMS m/z 466.0 (M+H)⁺.

Preparation of Intermediate 323a Ethyl 4-[4-(difluoromethyl)phenoxy]-2-methyl-1-benzofuran-6-carboxylate

A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (252c) (1.10 g, 5 mmol), 1-bromo-4-(difluoromethyl)benzene (1.24 g, 6 mmol), Cs₂CO₃ (2.44 g, 7.5 mmol) and CuI (5 mg, 0.03 mmol) in DMF (5 mL) was heated in a microwave at 160° C. for 60 minutes. Water was then added and the product was extracted with CHCl₃ (3×), dried over MgSO₄ and concentrated to give an oil residue. The oil was purified via silica gel chromatography using hexanes/EtOAc (100/0 to70/30) to give the title compound (710 mg, 41%) as a yellow solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.06 Hz, 3 H) 2.44 (s, 3 H) 4.37 (q, J=7.06 Hz, 2 H) 6.22 (d, J=0.94 Hz, 1 H) 6.63 (t, J=56.61 Hz, 1 H) 7.03 (d, J=8.29 Hz, 2 H) 7.46 (d, J=8.29 Hz, 2 H) 7.55 (d, J=1.13 Hz, 1 H) 7.89-8.05 (m, 1 H).

Preparation of Intermediate 323b Ethyl 2-(bromomethyl)-4-[4-(difluoromethyl)phenoxy]-1-benzofuran-6-carboxylate

To a solution of ethyl 4-[4-(difluoromethyl)phenoxy]-2-methyl-1-benzofuran-6-carboxylate (710 mg, 2.05 mmol) and NBS (438 mg, 2.46 mmol) in CHCl₃ (25 mL) was added benzoyl peroxide (49.7 mg, 0.205 mmol). The mixture was refluxed for 14 hours. The solvent was evaporated, and the product was purified via gradient silica gel chromatography using hexanes/EtOAc (100/0 to 70/30) to give the title compound (440 mg, 51%) as a light-yellow solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 4.38 (q, J=7.16 Hz, 2 H) 4.53 (s, 2 H) 6.39-6.89 (m, 2 H) 7.07 (d, J=8.48 Hz, 2 H) 7.49 (d, J=8.48 Hz, 2 H) 7.54 (d, J=0.94 Hz, 1 H) 8.01 (s, 1 H).

Preparation of Intermediate 323c Ethyl 4-[4-(difluoromethyl)phenoxy]-2-formyl-1-benzofuran-6-carboxylate

A solution of ethyl 2-(bromomethyl)-4-[4-(difluoromethyl)phenoxy]-1-benzofuran-6-carboxylate (440 mg, 1.03 mmol) and IBX (579 mg, 2.07 mmol) in DMSO (2 mL) was heated at 65° C. for 3 h. The reaction was quenched with water and the product was extracted with CHCl₃ (3×). The combined organic layers was washed with water (2×), dried over MgSO₄ and concentrated. The product was purified via gradient silica gel chromatography using hexanes/EtOAc (100/0 to 50/50) to give the title compound (300 mg, 81%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.39 (t, J=7.16 Hz, 3 H) 4.39 (q, J=7.16 Hz, 2 H) 6.67 (t, J=56.42 Hz, 1 H) 7.11-7.18 (m, J=8.67 Hz, 2 H) 7.48 (d, J=0.94 Hz, 1 H) 7.51 (d, J=0.94 Hz, 1 H) 7.55 (d, J=8.67 Hz, 2 H) 8.08 (d, J=0.94 Hz, 1 H) 9.87 (s, 1 H).

Preparation of Intermediate 323d 4-[4-(Difluoromethyl)phenoxy]-6-(ethoxycarbonyl)-1-benzofuran-2-carboxylic acid

To acetonitrile (10 mL) was added periodic acid (209 mg, 0.916 mmol) and stirred vigorously at room temperature for 15 min. Ethyl 4-[4-(difluoromethyl)phenoxy]-2-formyl-1-benzofuran-6-carboxylate (300 mg, 0.833 mmol) was then added (in ice-bath) followed by addition of pyridium fluorochromate (3.32.mg, 0.02 mmol) in CH₃CN (5 mL). The reaction was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with brine/water (1:1), dried over MgSO₄ and concentrated to give the title compound (300 mg, 96%) as an orange solid, which was usedin the next step without further purification. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.33 (t, J=7.16 Hz, 3 H) 4.33 (q, J=7.16 Hz, 2 H) 6.61 (t, J=56.52 Hz, 1 H) 7.06 (d, J=8.48 Hz, 2 H) 7.37 (s, 1 H) 7.43-7.54 (m, 3 H) 8.02 (s, 1 H).

Preparation of Intermediate 323e Ethyl 4-[4-(difluoromethyl)phenoxy]-2-[(dimethylamino)-carbonyl]-1-benzofuran-6-carboxylate

To a solution of 4-[4-(difluoromethyl)phenoxy]-6-(ethoxycarbonyl)-1-benzofuran-2-carboxylic acid (300 mg, 0.80 mmol) in DMF (10 mL) was added HATU (606 mg, 1.59 mmol), DIEA (515 mg, 4.0 mmol) and the solution was stirred at 0° C. for 15 min. Dimethylamine hydrochloride (97.5 mg, 1.20 mmol) was added and the solution was warmed gradually to room temperature and stirred for 14 h. Water was added to the reaction and the product was extracted with CHCl₃. The combined organic layers were washed with water twice, dried over MgSO₄, and concentrated. The product was purified via gradient silica gel chromatography using CHCl₃/MeOH (100/0 to 95/5) to give the title compound (240 mg, 70%) as a light yellow solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 3.13 (s, 3 H) 3.32 (s, 3 H) 4.38 (q, J=7.16 Hz, 2 H) 6.64 (t, J=56.61 Hz, 1 H) 7.09 (d, J=8.48 Hz, 2 H) 7.16 (s, 1 H) 7.50 (d, J=8.48 Hz, 2 H) 7.55 (s, 1 H) 8.05 (s, 1 H).

Preparation of Intermediate 323f 4-(4-Formylphenoxy)-N²,N²-dimethyl-N⁶-(5-methylpyridin-2yl)-1-benzofuran-2,6-dicarboxamide

2-Amino-5-methyl pyridine (214 mg, 1.98 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH₃)₂Cl (1.98 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 4-[4-(difluoromethyl)-phenoxy]-2-[(dimethylamino)carbonyl]-1-benzofuran-6-carboxylate (80 mg, 0.2 mmol) was added, and the stirring was continued for an additional 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl₃, washed with brine and dried over MgSO₄. The product was purified by chromatography on silica gel to give the title compound (40 mg, 45%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.26 (s, 3 H) 3.12 (s, 3 H) 3.31 (s, 3 H) 7.10 (d, J=8.67 Hz, 2 H) 7.15 (s, 1 H) 7.48 (d, J=1.13 Hz, 1 H) 7.54 (dd, J=8.48, 2.17 Hz, 1 H) 7.86 (d, J=8.67 Hz, 2 H) 7.95 (s, 1 H) 8.01 (s, 1 H) 8.22 (d, J=8.48 Hz, 1 H) 8.94 (s, 1 H) 9.92 (s, 1 H).

Example 324 N,N-Dimethyl-3-[(2-methyl-6-{[(5-methylpyridin-2-yl)amino]-carbonyl}-1-benzofuran-4-yl)oxy]azetidine-1-carboxamide

To a solution of 2-amino-5-methyl pyridine (203 mg, 1.88 mmol) in dichloromethane (5 mL) at 0° C. was added Al(CH₃)₂Cl (1.88 mL, 1M in hexanes) drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 4-({1-[(dimethylamino)carbonyl]azetidin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (65 mg, 0.19 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl₃, washed with brine and dried over Na₂SO₄. The product was purified by gradient silica gel chromatography using CHCl₃/MeOH (95/5 to 85/15) to give the title compound (70 mg, 90%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 3 H) 2.37 (s, 3 H) 2.78 (s, 6 H) 3.30-3.44 (m, 2 H) 3.44-3.60 (m, 1 H) 3.88 (dd, J=12.13, 6.06 Hz, 1 H) 4.05 (dd, J=11.75, 2.40 Hz, 1 H) 6.70 (s, 1 H) 6.98 (d, J=9.60 Hz, 1 H) 7.71-7.85 (m, 1 H) 7.92 (s, 1 H) 8.17 (d, J=8.34 Hz, 1 H) 8.28-8.44 (m, 2 H); MS (ESI, pos): 409.

Preparation of Intermediate 324a Ethyl 4-{[1-(diphenylmethyl)azetidin-3-yl]oxy}-2-methyl-1-benzofuran-6-carboxylate

A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (252c) (1.70 g, 7.72 mmol), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (193a) (2.95 g, 9.29 mmol) and Cs₂CO₃ (6.29 g, 19.3 mmol) in DMF (10 mL) was stirred for 4 hours at 100° C. The reaction was cooled to room temperature, diluted with EtOAc and washed with water and brine, dried over MgSO₄, and concentrated under reduced pressure. The product was purified via gradient silica gel chromatography using EtOAc/Hexanes (10/90 to 40/60) to give the desired compound (2.15 g, 63%) as a white solid after evaporation of the solvent. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32-1.49 (m, 3 H) 2.42-2.57 (m, 3 H) 3.10-3.29 (m, 2 H) 3.75-3.94 (m, 2 H) 4.27-4.42 (m, 2 H) 4.43-4.52 (m, 1 H) 4.91-5.10 (m, 1 H) 6.50 (s, 1 H) 7.05 (s, 1 H) 7.15-7.25 (m, 2 H) 7.24-7.35 (m, 4 H) 7.39-7.54 (m, 4 H) 7.74 (s, 1 H); MS (ESI, pos): 442.

Preparation of Intermediate 324b Ethyl 4-(azetidin-3-yloxy)-2-methyl-1-benzofuran-6-carboxylate

A mixture of ethyl 4-{[1-(diphenylmethyl)azetidin-3-yl]oxy}-2-methyl-1-benzofuran-6-carboxylate (2.1 g, 4.77 mmol) in EtOAc/MeOH (10 mL/20 mL) and Pd/C (0.060 g, 10%, 0.048 mmol) was stirred for 14 hours under a hydrogen atmosphere (balloon). The mixture was filtered through a bed of Celite washing with methanol. The sample was concentrated to give a pale white solid (quantitative yield), which was used without further purification. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35-1.52 (m, 3 H) 2.18 (s, 1 H) 2.47 (s, 3 H) 3.78-3.94 (m, 2 H) 4.00-4.13 (m, J=7.16 Hz, 2 H) 4.29-4.49 (m, 2 H) 5.11-5.27 (m, 1 H) 6.52 (s, 1 H) 7.05 (s, 1 H) 7.78 (s, 1 H); MS (ESI, pos): 276.

Preparation of Intermediate 324c Ethyl 4-({1-[(dimethylamino)carbonyl]azetidin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate

To a solution of ethyl 4-(azetidin-3-yloxy)-2-methyl-1-benzofuran-6-carboxylate (200 mg, 0.73 mmol) in dissolved in DCM with containing TEA (0.4 mL, 2.9 mmol) was added dimethylcarbamic chloride (0.1 mL, 1.09 mmol). The mixture solution was stirred at room temperature for 2 hrs. The reaction was diluted with DCM, washed with NaHCO₃, brine, dried over Na₂SO₄ and concentrated under reduced pressure. The product was purified via gradient silica gel chromatography using EtOAc/Hexanes (20/80 to 60/40) to provide the product (138 mg, 55%) as a colorless oil. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36-1.54 (m, 3 H) 2.49 (s, 3 H) 2.88 (s, 6 H) 4.06-4.20 (m, 2 H) 4.33-4.53 (m, 4 H) 5.04-5.18 (m, 1 H) 6.52 (s, 1 H) 7.01 (s, 1 H) 7.80 (s, 1 H); MS (ESI, pos): 347.

Example 325 2-Methyl-4-{[1-(methylsulfonyl)azetidin-3-yl]oxy}-N-(2-methyl-2H-1,2,3-triazol-4-yl)-1-benzofuran-6-carboxamide

To a solution of 2-methyl-2H-1,2,3-triazol-4-amine (267 mg, 1.98 mmol) in dichloromethane (5 mL) at 0° C. was added Al(CH₃)₂Cl (1.98 mL, 1.98 mmol, 1M in hexanes) drop-wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-methyl-4-{[1-(methylsulfonyl)azetidin-3-yl]oxy}-1-benzofuran-6-carboxylate (70 mg, 0.198 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CH₂Cl₂, washed with brine and dried over Na₂SO₄. The product was purified by gradient silica gel chromatography using CHCl₃/MeOH (95/5 to 85/15) to give the title compound (55 mg, 68%) as a white solid after evaporation of the solvents. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3 H) 2.94 (s, 3 H) 4.06-4.15 (m, 3 H) 4.16 (d, J=4.80 Hz, 2 H) 4.39 (dd, J=9.60, 6.32 Hz, 2 H) 5.05-5.23 (m, 1 H) 6.54 (s, 1 H) 6.97 (s, 1 H) 7.54 (s, 1 H) 8.12 (s, 1 H) 8.46 (s, 1 H); MS (ESI, pos): 406.

Preparation of Intermediate 325a Ethyl 2-methyl-4-{[1-(methylsulfonyl)azetidin-3-yl]oxy}-1-benzofuran-6-carboxylate

To a solution of ethyl 4-(azetidin-3-yloxy)-2-methyl-1-benzofuran-6-carboxylate (324b) (200 mg, 0.73 mmol) in DCM containing TEA (0.4 mL, 2.9 mmol) was added methanesulfonyl chloride (0.07 mL, 0.87 mmol). The mixture was stirred at room temperature for 2 hrs. The reaction was diluted with DCM, washed with NaHCO₃, brine, dried over Na₂SO₄ and concentrated under reduced pressure. The product was purified via gradient silica gel chromatography using EtOAc/Hexanes (10/90 to 30/70) to provide the product (206 mg, 80%) as a white solid after evaporation of the solvents. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.34-1.51 (m, 3 H) 2.49 (s, 3 H) 2.89-3.07 (m, 3 H) 4.06-4.22 (m, J=9.23, 4.33 Hz, 2 H) 4.33-4.54 (m, 4 H) 5.07-5.23 (m, 1 H) 6.52 (s, 1 H) 7.02 (s, 1 H)l MS (ESI, pos): 354.

Example 326 and 327 were prepared in a similar manner as described for Example 325, from Intermediate 325a and the appropriate amino heterocycles.

Example 326 2-Methyl-N-(5-methylpyridin-2-yl)-4-{[1-(methylsulfonyl)-azetidin-3-yl]oxy}-1-benzofuran-6-carboxamide

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.34 (s, 3 H) 2.51 (s, 3 H) 2.95 (s, 3 H) 4.08-4.23 (m, 2 H) 4.34-4.50 (m, 2 H) 5.10-5.26 (m, 1 H) 6.54 (s, 1 H) 6.98 (s, 1 H) 7.57-7.70 (m, 2 H) 8.14 (s, 1 H) 8.27 (d, J=8.67 Hz, 1 H) 8.57 (s, 1 H); LCMS m/z 416 (M+H)⁺.

Example 327 2-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-4-{[1-(methylsulfonyl)-azetidin-3-yl]oxy}-1-benzofuran-6-carboxamide

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.45-2.69 (m, 3 H) 2.85-3.13 (m, 3 H) 3.64-3.83 (m, 3 H) 4.11 (dd, J=9.09, 4.80 Hz, 2 H) 4.35 (dd, J=8.97, 6.44 Hz, 2 H) 4.95-5.24 (m, 1 H) 6.85 (s, 1 H) 6.95 (s, 1 H) 7.31 (d, J=2.27 Hz, 1 H) 7.56 (s, 1 H) 9.04 (s, 1 H); LCMS m/z 405 (M+H)⁺.

Example 328 2-Methyl-7-(1-methyl-2-phenylethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-1-benzothiophene-5-carboxamide

3-Amino-1-methyl pyrazole (649 mg, 6.69 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH₃)₂Cl (6.69 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 min at room temperature. Ethyl 2-methyl-7-[(1S)-1-methyl-2-phenylethoxy]-1-benzothiophene-5-carboxylate (237 mg, 0.669 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl₃, washed with brine and dried over MgSO₄. The product was purified by reverse phase HPLC to give the title compound (155 mg, 57%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (d, J=6.03 Hz, 3 H) 2.59 (s, 3 H) 2.95 (dd, J=13.75, 6.22 Hz, 1 H) 3.16 (dd, J=13.75, 6.03 Hz, 1 H) 3.74 (s, 3 H) 4.78-5.01 (m, 1 H) 6.89 (d, J=2.26H) 7.00 (d, J−1.13 Hz, 1 H) 7.12-7.23 (m, 1 H) 7.26-7.42 (m, 6 H) 7.81 (d, J=1.13 Hz, 1 H) 9.60 (s, 1 H). LCMS m/z 406.0 (M+H)⁺.

Preparation of Intermediate 328a 5-Methylthiophene-3-carbaldehyde

To a solution of N-methylpiperazine (32.5 g, 36 mL, 0.33 mol) in THF (500 mL) at −78° C. was added drop-wise a solution of n-BuLi (1.6 M in hexane, 210 mL). The mixture was stirred for 0.25 h, and 3-thiophenecarbaldehyde (30 g, 0.27 mol) was added drop-wise. The mixture was stirred for 15 min more. TMEDA (81 mL, 63 g, 0.54 mol) and then sec-BuLi (1.3 M in cyclohexane, 250 mL) were added. The mixture was stirred at −78° C. for 2 h. Methyl iodide (153 g, 67 mL, 1.08 mol) was added drop-wise. The mixture was allowed to come to room temperature, stirred overnight, poured into cold water (1 L), and extracted with ether (1 L). The ethereal layer was washed with brine, dried with Na₂SO₄, and evaporated in vacuum. The crude product was purified on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, (5:1). Fractions with the target product were collected and evaporated in vacuum to give 26 g (0.2 mol, 76%) of a mixture of the desired product and 2-methylthiopene-3-carbaldehyde in 9:1 ratio as a colorless liquid.

Preparation of Intermediate 328b 3-(Ethoxycarbonyl)-4-(5-methyl-3-thienyl)but-3-enoic Acid

Sodium ethylate (17 g, 0.24 mol) was added under vigorous stirring to a solution of 5-methylthiophene-3-carbaldehyde (26 g 90% purity, 0.20 mol) and diethyl succinate (54 g, 0.31 mol) in ethanol (400 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 300 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 700 mL of a saturated aqueous solution of NaHCO₃, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. The residue was chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture (1:1). Fractions with the target product were collected and evaporated in vacuum to give the desired product 30 g (0.12 mol, 57%) as an oil.

Preparation of Intermediate 328c Ethyl 7-(Acetyloxy)-2-methyl-1-benzothiophene-5-carboxylate

Sodium acetate (30 g, 0.36 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-3-thienyl)but-3-enoic acid (30 g, 0.12 mol) in 300 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO₃ and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 14 g (50 mmol, 42%) as a solid.

Preparation of Intermediate 328d Ethyl 7-Hydroxy-2-methyl-1-benzothiophene-5-carboxylate

Ethyl 7-(acetyloxy)-2-methyl-1-benzothiophene-5-carboxylate was dissolved in absolute ethanol (500 mL). Potassium carbonate (18 g, 0.13 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The residue was crystallized from ether/hexane mixture (1:5) to give the desired product 10 g (42 mmol, 84%) as a cream solid. ¹H NMR (DMSO-d6): δ ppm 1.30 (t, 3H), 2.50 (s, 3H), 4.30 (qt, 2H), 7.20 (s, 1H), 7.95(s, 1H), 7.85 (s, 1H); MS(APCl, pos): 237.1.

Preparation of Intermediate 328e Ethyl 2-methyl-7-(1-methyl-2-phenylethoxy)-1-benzothiophene-5-carboxylate

To a solution of ethyl 7-hydroxy-2-methyl-1-benzothiophene-5-carboxylate (500 mg, 2.12 mmol), Ph₃P (1110 mg, 4.23 mmol) and 1-phenyl-2-propane (576 mg, 4.23 mmol) in CH₂Cl₂ (20 mL) was added DIAD (856 mg, 4.23 mmol) drop wise at 0° C. The resulting solution was stirred at room temperature for 4 h. The reaction mixture was concentrated to give an oil residue. The residue was purified by HPLC to give the title compound (500 mg, 67%) as a colorless oil. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.36-1.47 (m, 6 H) 2.59 (d, J=1.13 Hz, 3 H) 2.84-3.00 (m, 1 H) 3.10-3.27 (m, 1 H) 4.38 (q, J=7.16 Hz, 2 H) 4.71-4.93 (m, 1 H) 7.01 (d, J=1.13 Hz, 1 H) 7.26-7.33 (m, 5 H) 7.35 (s, 1 H) 7.97 (d, J=1.13 Hz, 1 H).

Examples 329 and 330 were prepared in a similar manner as described for Example 252, via two steps, from Intermediate 328d.

Example 329 2-Methyl-N-(5-methylpyridin-2-yl)-7-[4-(methylsulfonyl)-phenoxy]-1-benzothiophene-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.38 (s, 3 H) 2.61 (s, 3 H) 3.06 (s, 3 H) 7.09-7.23 (m, 3 H) 7.55 (s, 1 H) 7.80 (d, J=8.85 Hz, 1 H) 7.86-7.99 (m, 2 H) 8.08 (s, 1 H) 8.21 (s, 1 H) 8.51 (d, J=8.85 Hz, 1 H) 10.52 (s, 1 H); LCMS m/z 453.0 (M+H)⁺.

Example 330 2-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-7-[4-(methylsulfonyl)-phenoxy]-1-benzothiophene-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.60 (s, 3 H) 3.06 (s, 3 H) 3.80 (s, 3 H) 6.85 (d, J=2.26 Hz, 1 H) 7.12 (d, J=1.13 Hz, 1 H) 7.14-7.23 (m, 2 H) 7.28 (d, J=2.26 Hz, 1 H) 7.53 (d, J=1.51 Hz, 1 H) 7.81-7.98 (m, 2 H) 8.14 (d, J=1.32 Hz, 1 H) 9.62 (s, 1 H); LCMS m/z 442.0 (M+H)⁺.

Example 331 7-{4-[(Dimethylamino)carbonyl]phenoxy}-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)-1-benzothiophene-5-carboxamide

The title compound was prepared in a similar manner as described for Example 276, via three steps from Intermediate 328d. ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.59 (s, 3 H) 3.07 (s, 6 H) 3.75 (s, 3 H) 6.81 (d, J=2.26 Hz, 1 H) 6.97-7.14 (m, 3 H) 7.27 (d, J=2.26 Hz, 1 H) 7.35-7.52 (m, 3 H) 7.99 (d, J−1.13 Hz, 1 H) 9.22 (s, 1 H); LCMS m/z 435.0 (M+H)⁺.

Examples 332 and 333 were prepared in a similar manner as described for Example 252, via two steps, from ethyl 7-hydroxybenzofuran-5-carboxylate (332c).

Preparation of Intermediate 332a 3-(Ethoxycarbonyl)-4-(furan-3-yl)but-3-enoic acid

Sodium ethylate (6.5 g, 95 mmol) was added under vigorous stirring to a solution of 2-furaldehyde (10 g, 79 mmol) and diethyl succinate (27.6 g, 158 mmol) in ethanol (300 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 200 mL of 10% HCl and 300 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 200 mL of a saturated aqueous solution of NaHCO₃, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 400 mL of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture (1:1). Fractions containing the target product were collected and evaporated in vacuum to give the product 9.3 g (38 mmol, 49%) as a light-brown oil.

Preparation of Intermediate 332b Ethyl 7-(Acetyloxy)-1-benzofuran-5-carboxylate

Sodium acetate (10 g, 120 mmol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(furan-3-yl)but-3-enoic acid (12.3 g, 48 mmol) in 100 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 250 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a saturated aqueous solution of NaHCO₃ and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 5.2 g (29 mmol, 61%) as a yellow solid.

Preparation of Intermediate 332c Ethyl 7-Hydroxy-1-benzofuran-5-carboxylate

Ethyl 7-(Acetyloxy)-1-benzofuran-5-carboxylate was dissolved in absolute ethanol (200 mL). Potassium carbonate (7 g, 50 mmol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (2:1) to give the desired product 2.8 g (13 mmol, 38%) as a cream solid. ¹H NMR (DMSO-D6): δ ppm 1.35 (s, 3H), 4.20 (qt, 2H), 7.15 (m ,1H), 7.39 (m, 1H), 7.77 (m, 1H), i8.04 (m, 1H); MS (APCI, pos): 241.1.

Example 332 N-(1-Methyl-1H-pyrazol-3-yl)-7-[4-(methylsulfonyl)phenoxy]-1-benzofuran-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 3.06 (s, 3 H) 3.77 (s, 3 H) 6.82 (d, J=2.26 Hz, 1 H) 6.90 (d, J=2.07 Hz, 1 H) 7.05-7.20 (m, 2 H) 7.29 (d, J=2.26 Hz, 1 H) 7.63 (d, J=1.51 Hz, 1 H) 7.67 (d, J=2.07 Hz, 1 H) 7.84-7.97 (m, 2 H) 8.02 (d, J=1.51 Hz, 1 H) 9.02 (s, 1 H); LCMS m/z 412.0 (M+H)⁺.

Example 333 N-(5-methylpyridin-2-yl)-7-[4-(methylsulfonyl)phenoxy]-1-benzofuran-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.42 (s, 3 H) 3.06 (s, 3 H) 6.96 (d, J=2.07 Hz, 1 H) 7.12-7.23 (m, 2 H) 7.69 (d, J=2.07 Hz, 1 H) 7.77 (d, J=1.51 Hz, 1 H) 7.84-8.00 (m, 3 H) 8.06 (s, 1 H) 8.26 (d, J=1.51 Hz, 1 H) 8.64 (d, J=8.85 Hz, 1 H) 11.57 (s, 1 H); LCMS m/z 423.0 (M+H)⁺.

Examples 334 and 335 were prepared in a similar manner as described for Example 276, via three steps, from ethyl 7-hydroxybenzofuran-5-carboxylate (332c).

Example 334 7-{4-[(Dimethylamino)carbonyl]phenoxy}-N-(1-methyl-1H-pyrazol-3-yl)-1-benzofuran-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 3.06 (d, J=9.04 Hz, 6 H) 3.74 (s, 3 H) 6.80 (d, J=2.07 Hz, 1 H) 6.87 (d, J=2.26 Hz, 1 H) 7.04 (d, J=8.48 Hz, 2 H) 7.27 (d, J=2.26 Hz, 1 H) 7.42 (d, J=8.48 Hz, 2 H) 7.52 (s, 1 H) 7.67 (d, J=2.07 Hz, 1 H) 7.93 (d, J=1.32 Hz, 1 H) 8.89 (s, 1 H); LCMS m/z 405.0 (M+H)⁺.

Example 335 7-{4-[(Dimethylamino)carbonyl]phenoxy}-N-(5-methylpyridin-2-yl)-1-benzofuran-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.31 (s, 3 H) 3.08 (s, 6 H) 6.90 (d, J=2.26 Hz, 1 H) 7.05 (d, J=8.67 Hz, 2 H) 7.38-7.47 (d, J=8.67 Hz, 2 H) 7.57 (s, 1 H) 7.61 (d, J=8.48 Hz, 1 H) 7.69 (d, J=2.26 Hz, 1 H) 8.02 (d, J=1.51 Hz, 1 H) 8.09 (s, 1 H) 8.23 (d, J=8.48 Hz, 1 H) 8.91 (s, 1 H); LCMS m/z 416.0 (M+H)⁺.

Example 336 7-[(1S)-1-Methyl-2-phenylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-1-benzofuran-5-carboxamide

The title compound was prepared in a similar manner as described for Example 328, via two steps, from ethyl 7-hydroxybenzofuran-5-carboxylate (332c). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (d, J=6.03 Hz, 3 H) 2.92 (dd, J=13.75, 6.78 Hz, 1 H) 3.22 (dd, J=13.56, 6.03 Hz, 1 H) 3.66 (s, 3 H) 4.85-5.03 (m, 1 H) 6.79 (d, J=2.26 Hz, 1 H) 6.89 (d, J=2.26 Hz, 1 H) 7.12-7.24 (m, 1 H) 7.25-7.36 (m, 5 H) 7.46 (s, 1 H) 7.67 (d, J=2.07 Hz, 1 H) 7.73 (d, J=1.32 Hz, 1 H) 9.71 (s, 1 H); LCMS m/z 376.0 (M+H)⁺.

Examples 337 and 338 were prepared in a similar manner as described for Example 252, via two steps, from ethyl 7-hydroxy-2-methylbenzofuran-5-carboxylate (337d).

Preparation of Intermediate 337a 5-Methyl-3-furaldehyde

To a solution of N-methylpiperazine (31 g, 35 mL, 0.31 mol) in THF (500 mL) at −78° C. was added drop-wise a solution of n-BuLi (1.6 M in hexane, 200 mL). The mixture was stirred for 0.25 h, and 3-furaldehyde (25 g, 0.26 mol) was added drop-wise. The mixture was stirred for 0.25 h more. TMEDA (77 mL, 60g, 0.52 mol) and then sec-BuLi (1.3 M in cyclohexane, 250 mL) were added, and the mixture was stirred at −78° C. for 2 h. Methyl iodide (148 g, 65 mL, 1.04 mol) was added drop-wise. The mixture was allowed to come to room temperature, stirred overnight, poured into cold water (1 L), and extracted with ether (1L). The ethereal layer was washed with brine, dried with Na₂SO₄, and evaporated in vacuum. The crude product was purified on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, 5:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give 21 g (0.19 mol, 74%) of a mixture of the desired product and 2-methyl-3-furaldehyde in 4:1 ratio as a colorless liquid.

Preparation of Intermediate 337b 3-(Ethoxycarbonyl)-4-(5-methyl-3-furyl)but-3-enoic Acid

Sodium ethylate (16 g, 0.23 mol) was added under vigorous stirring to a solution of 5-methyl-3-furaldehyde (21 g 80% purity, 0.19 mol) and diethyl succinate (50 g, 0.286 mol) in ethanol (400 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 300 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 700 mL of a saturated aqueous solution of NaHCO₃, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture (1:1). Fractions with the target product were collected, evaporated in vacuum and crystallized from ether/hexane mixture, 1:3 to give the desired product 14 g (58 mmol, 31%) as yellow crystals.

Preparation of Intermediate 337c Ethyl 7-(Acetyloxy)-2-methyl-1-benzofuran-5-carboxylate

Sodium acetate (15 g, 0.18 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-3-furyl)but-3-enoic acid (14 g, 58 mmol) in 150 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 300 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO₃ and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) as eluent to give the desired product 12.5 g (47 mmol, 81%) as a solid.

Preparation of Intermediate 337d Ethyl 7-Hydroxy-2-methyl-1-benzofuran-5-carboxylate

Ethyl 7-(Acetyloxy)-2-methyl-1-benzofuran-5-carboxylate was dissolved in absolute ethanol (200 mL).

Potassium carbonate (18 g, 0.13 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The residue was and crystallized from ether/hexane mixture, 1:5 to give the desired product 8.5 g (38 mmol, 81%) as a cream solid. ¹H NMR (DMSO-D6): δ ppm 1.35 (t, 3H), 2.40 (s, 3H), 4.20 (qt, 2H), 6.65 (s, 1H), 7.32 (s, 1H), 7.65 (s, 1H); MS (APCI, pos): 221.1.

Example 337 2-Methyl-N-(5-methylpyridin-2-yl)-7-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.30 (s, 3 H) 2.45 (s, 3 H) 3.06 (s, 3 H) 6.52 (d, J=0.94 Hz, 1 H) 7.07-7.21 (m, 2 H) 7.47-7.65 (m, 2 H) 7.84-8.00 (m, 3 H) 8.10 (s, 1 H) 8.24 (d, J=8.29 Hz, 1 H) 8.59 (s, 1 H); LCMS m/z 437.0 (M+H)⁺.

Example 338 2-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-7-[4-(methylsulfonyl)-phenoxy]-1-benzofuran-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.45 (s, 3 H) 3.06 (s, 3 H) 3.78 (s, 3 H) 6.52 (d, J=1.13 Hz, 1 H) 6.84 (d, J=2.26 Hz, 1 H) 7.08-7.22 (m, 2 H) 7.28 (d, J=2.26 Hz, 1 H) 7.59 (d, J=1.70 Hz, 1 H) 7.83-7.95 (m, 2 H) 7.97 (d, J=1.70 Hz, 1 H) 9.65 (s, 1 H); LCMS m/z 426.0 (M+H)⁺.

Example 339 7-{4-[(Dimethylamino)carbonyl]phenoxy}-2-methyl-N-(5-methylpyridin-2-yl)-1-benzofuran-5-carboxamide

The title compound was prepared in a similar manner as described for Example 276, via three steps, from ethyl 7-hydroxy-2-methylbenzofuran-5-carboxylate (337d). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.30 (s, 3 H) 2.46 (s, 3 H) 3.06 (d, J=11.11 Hz, 6 H) 6.51 (s, 1 H) 7.01-7.15 (m, 2 H) 7.38-7.45 (m, 2 H) 7.46 (d, J=1.51 Hz, 1 H) 7.59 (dd, J=8.48, 2.07 Hz, 1 H) 7.88 (d, J=1.51 Hz, 1 H) 8.08 (s, 1 H) 8.23 (d, J=8.48 Hz, 1 H) 8.87 (s, 1 H); LCMS m/z 430.0 (M+H)⁺.

Example 340 2-Methyl-7-[(1S)-1-methyl-2-phenylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-1-benzofuran-5-carboxamide

The title compound was prepared in a similar manner as described for Example 328, via two steps, from ethyl 7-hydroxy-2-methylbenzofuran-5-carboxylate (337d). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (d, J=6.03 Hz, 3 H) 2.49 (s, 3 H) 2.91 (dd, J=13.56, 6.97 Hz, 1 H) 3.23 (dd, J=13.56, 6.03 Hz, 1 H) 3.72 (s, 3 H) 4.78-4.97 (m, 1 H) 6.39 (d, J=0.94 Hz, 1 H) 6.84 (d, J=2.26 Hz, 1 H) 7.16-7.24 (m, 1 H) 7.26-7.31 (m, 5 H) 7.33 (d, J=1.51 Hz, 1 H) 7.54 (d, J=1.51 Hz, 1 H) 8.98 (s, 1 H); LCMS m/z 390.0 (M+H)⁺.

Example 341 4-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzofuran-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxy-benzofuran-6-carboxylate (8a) (0.256 g, 1.24 mmol) and 2,4-difluoro-N,N-dimethylbenzamide (0.287 g, 1.55 mmol) in DMF (5 mL). The mixture was stirred at 150° C. for 8 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.21 g, 2.11 mmol) and then HATU (0.71 g, 1.87 mmol) were added. The reaction mixture was stirred at 50° C. for one hour and then filtered. Purification by HPLC gave a solid (200 mg, 39% yield) as the expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1 H) 8.22 (s, 1 H) 8.16 (m, 1 H)) 7.62-7.36 (s, 1 H) 7.60-7.61 (m, 1 H) 7.39-7.43 (m, 1 H) 7.08-7.11 (m, 1 H) 6.95-6.97 (m, 1 H) 6.89 (s, 1 H) 6.59-6.60 (m, 1 H) 3.78 (s, 3 H) 2.99 (s, 3 H) 2.88 (m, 3 H). LCMS for C₂₂H₁₉FN₄O₄ m/z 423.10 (M+H)⁺.

Example 342 4-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-N-(5-methylpyridin-2-yl)benzofuran-6-carboxamide

The title compound was prepared in a similar manner as described for Example 341, from ethyl 4-hydroxy-benzofuran-6-carboxylate (8a) (0.26 g, 1.24 mmol), 2,4-difluoro-N,N-dimethylbenzamide (0.287 g, 1.55 mmol), and 2-amino-5-methyl pyridine (0.228 g, 2.11 mmol) (except that amide coupling was carried out at 75° C. for four hours) to give a solid (81 mg, 15% yield) as the expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1 H) 8.27 (s, 1 H) 8.22-8.23 (m, 1 H) 8.18-8.19 (m, 1 H)) 8.06-8.08 (d, 1 H) 7.67 (m, 1 H) 7.64 (m, 1 H) 7.39-7.44 (t, 1 H) 7.09-7.12 (m, 1 H) 6.95-6.97 (m, 1 H) 6.90 (m, 1 H) 3.00 (s, 3 H) 2.88 (m, 3 H) 2.28 (s, 3 H). LCMS for C₂₄H₂₀FN₃O₄ m/z 434.10 (M+H)⁺.

Example 343 4-(4-(Methylsulfonyl)phenoxy)-N-(1-methyl-1H-pyrazol-3-Abenzofuran-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxybenzofuran-6-carboxylate (8a) (0.27 g, 1.24 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (0.22 g, 1.26 mmol) in DMF (5 ML). The mixture was stirred at 120° C. for 8 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.18 g, 1.85 mmol) and HATU (0.7 g, 1.85 mmol) were added. The reaction mixture was stirred at 50° C. for one hour and then filtered. Purification by HPLC gave a solid (103 mg, 21% yield) as the expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1 H) 8.24-8.26 (m, 1 H) 8.17-8.19 (m, 1 H) 7.92-7.97 (m, 2 H) 7.65-7.67 (m, 1 H) 7.60-7.61 (m, 2 H) 7.25-7.29 (m, 1 H) 6.87-6.88 (m, 1 H) 6.58 (m, 1 H) 3.78 (s, 3 H), 3.21 (s, 3 H), 2.58 (m, 3 H). LCMS for C₂₀H₁₇N₃O₆S m/z 412.10 (M+H)⁺.

Example 344 6-Isopropoxy-N-(5-methylpyridin-2-yl)benzofuran-4-carboxamide

The title compound was prepared in a similar manner as described for Example 1, from 2-amino-5-methyl pyridine and methyl 6-isopropoxybenzofuran-4-carboxylate (344a) to give a white solid (28 mg, 37% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1 H) 8.29 (d, J=8.56 Hz, 1 H) 8.04 (d, J=2.52 Hz, 1 H) 7.65 (d, J=2.27 Hz, 1 H) 7.58 (dd, J=8.31, 2.27 Hz, 1 H) 7.34 (d, J=2.01 Hz, 1 H) 7.21-7.23 (m, 2 H) 4.55-4.64 (m, 1 H) 2.30 (s, 3 H) 1.37 (d, J=6.04 Hz, 6 H); LCMS for C₁₈H₁₈N₂O₃m/z 311.10 (M+H)⁺.

Preparation of Intermediate 344a Methyl 6-isopropoxybenzofuran-4-carboxylate

The title compound was prepared in a similar manner as described for Example 6c. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J=2.01 Hz, 1 H) 7.61 (d, J=2.27 Hz, 1 H) 7.26 (d, J=2.27 Hz, 1 H) 7.24 (d, J=2.27 Hz, 1 H) 4.59-4.66 (m, 1 H), 3.98 (s, 3H), 1.38 (d, J=6.04 Hz, 6 H); LCMS for C₁₃H₁₄O₄m/z 235.10 (M+H⁺).

Example 345 2-Bromo-6-isopropoxy-N-(5-methylpyridin-2-yl)benzofuran-4-carboxamide

The title compound was prepared in a similar manner as described for Example 1, from 2-amino-5-methyl pyridine and methyl 2-bromo-6-isopropoxybenzofuran-4-carboxylate (345a) to give an off-white solid (1.45 g, 53% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1 H) 8.27 (d, J=8.31 Hz, 1 H) 8.14 (s, 1 H) 7.60 (dd, J=8.44, 1.89 Hz, 1 H) 7.30 (d, J=2.01 Hz, 1 H) 7.24 (s, 1 H) 7.16 (d, J=1.76 Hz, 1 H) 4.57-4.64 (m, 1 H) 2.34 (s, 3 H) 1.38 (d, J=6.04 Hz, 6 H); LCMS for C₁₈H₁₇BrN₂O₃m/z 389.00(M+H)⁺.

Preparation of Intermediate 345a Methyl 2-bromo-6-isopropoxybenzofuran-4-carboxylate

A mixture of methyl 6-isopropoxybenzofuran-4-carboxylate (344a) (2.17 g, 9.25 mmol) and NBS (4.12 g, 23.1 mmol) in 50 mL of CHCl₃ was heated at 60° C. for 5 hrs, followed by addition of another batch of NBS (2.50 g, 14.0 mmol). After stirring for an additional 1.2 h, the reaction was concentrated, and the residue was purified with Biotage column chromatography eluting with CHCl₃ to give a yellow oil (2.52 g, 87% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=2.27 Hz, 1 H) 7.22 (s, 1 H) 7.18 (d, J=2.01 Hz, 1 H) 4.56-4.64 (m, 1 H), 3.97 (s, 3H), 1.37 (d, J=6.04 Hz, 6 H); LCMS for C₁₃H₁₃BrO₄m/z 312.0 (M+H⁺).

Example 346 6-Isopropoxy-N-(5-methylpyridin-2-yl)-2-(prop-1-en-2-yl)benzofuran-4-carboxamide

A solution of 2-bromo-6-isopropoxy-N-(5-methylpyridin-2-yl)benzofuran-4-carboxamide (263 mg, 0.68 mmol), isopropenyl boronic acid (58.4 mg, 0.68 mmol), Pd(PPh₃)₂Cl₂ (23.9 mg, 0.034 mmol) and aqueous Na₂CO₃ (1.0 M in H₂O, 1.36 mL) in 1.4 mL of CH₃CN was heated in a microwave reactor at 150° C. for 5 min. The solvent was removed in vacuo. The residue was purified with Biotage column chromatography to give a light yellow solid (102 mg, 43% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s, 1 H) 8.30 (d, J=8.56 Hz, 1 H) 7.96 (d, J=2.01 Hz, 1 H) 7.56 (dd, J=8.56, 2.27 Hz, 1 H) 7.26 (d, J=2.27 Hz, 1 H) 7.14 (d, J=1.51 Hz, 1 H) 7.09 (s, 1 H) 5.76 (s, 1 H) 5.17 (s, 1 H) 4.53-4.59 (m, 1 H) 2.27 (s, 3H) 2.11 (s, 3 H) 1.36 (d, J=6.04 Hz, 6 H); LCMS for C₂₁H₂₂N₂O₃ m/z 351.10 (M+H)⁺.

Example 347 6-Isopropoxy-N-(5-methylpyridin-2-yl)-2-phenylbenzofuran-4-carboxamide

The title compound was prepared in a similar manner as described for Example 346. ¹H NMR (400 MHz, CDCl₃) δ 8.82 (s, 1 H) 8.32 (d, J=8.56 Hz, 1 H) 8.08 (d, J=2.27 Hz, 1 H) 7.85-7.89 (m, 2 H) 7.59 (dd, J=8.56, 2.27 Hz, 1 H) 7.52 (s, 1 H) 7.45 (t, J=7.55 Hz, 2 H) 7.36 (t, J=7.30 Hz, 1 H) 7.32 (d, J=2.01 Hz, 1 H) 7.24 (d, J=1.26 Hz, 1 H) 4.58-4.65 (m, 1 H) 2.31 (s, 3H) 1.39 (d, J=6.04 Hz, 6 H); LCMS for C₂₄H₂₂N₂O₃ m/z 387.10 (M+H)⁺.

Example 348 6-Isopropoxy-2-isopropyl-N-(5-methylpyridin-2-yl)benzofuran-4-carboxamide

A solution of 6-isopropoxy-N-(5-methylpyridin-2-yl)-2-(prop-1-en-2-yl)benzofuran-4-carboxamide (118 mg, 0.34 mmol) in 10 mL of MeOH was passed through H-cube (10 bar of H₂, 15° C., 5% Pd/C cartridge) at a rate of 1.0 mL/min. The collected solution was subsequently concentrated to give a light yellow gum (65 mg, 54%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1 H) 8.31 (d, J=8.56 Hz, 1 H) 8.14 (s, 1 H) 7.60 (dd, J=8.44, 2.14 Hz, 1 H) 7.29 (d, J=2.01 Hz, 1 H) 7.16 (d, J=2.01 Hz, 1 H) 6.84 (s, 1 H) 4.56-4.63 (m, 1 H), 3.04-3.13 (m, 1 H), 2.34 (s, 3H), 1.37 (m, 12 H); LCMS for C₂₁H₂₄N₂O₃ m/z 353.20 (M+H)⁺.

Example 349 2-(Azetidine-1-carbonyl)-6-isopropoxy-N-(5-methylpyridin-2-yl)benzofuran-4-carboxamide

A 0.5-2.0 mL microwave vial was charged with 2-bromo-6-isopropoxy-N-(5-methylpyridin-2-yl)benzofuran-4-carboxamide (156 mg, 0.40 mmol), Herrmann's palladacycle (20 mg, 0.02 mmol), Mo(CO)₆ (106 mg, 0.40 mmol), azetidine (80 μL, 1.2 mmol), DBU (180 1.2 mmol) and dry THF (1.0 mL). The vial was immediately sealed and irradiated with microwave to 150° C. for 15 min. After cooling, the reaction was concentrated, and the residue was purified with Biotage column chromatography twice, first eluting with EtOAc and then with 5% MeOH/CHCl₃, to give a white solid (62 mg, 39%). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1 H) 8.26 (d, J=8.31 Hz, 1 H) 8.12 (d, J=2.01 Hz, 1 H) 7.74 (s, 1 H) 7.59 (dd, J=8.31, 2.27 Hz, 1 H) 7.35 (d, J=2.01 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 4.59-4.67 (m, 3 H), 4.27 (t, J=7.43 Hz, 2 H) 2.39-2.48 (m, 2 H), 2.33 (s, 3H), 1.37 (d, J=6.04 Hz, 6 H); LCMS for C₂₂H₂₃N₃O₄ m/z 394.20 (M+H)⁺.

Examples 350 and 351 were prepared in a similar manner as described for Example 252, via two steps, from ethyl 4-hydroxy-3-methyl-1-benzothiophene-6-carboxylate (350d).

Preparation of Intermediate 350a 4-Methylthiopene-2-carbaldehyde

To a solution of 3-methylthiophene (75 g, 0.762 mol) in ether (750 mL) was added drop wise a solution of n-BuLi (1.6 M in hexane, 500 mL). The mixture was stirred for 1.5 h at room temperature. DMF (73 g, 1 mol) was then added. The reaction mixture was let to stir overnight, poured into saturated ammonium chloride (1 L), and extracted with ether (1 L). The ethereal layer was washed with brine, dried with Na₂SO₄, and evaporated in vacuum. The crude product was purified on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, 5:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give 88 g (0.7 mol, 91%) of a mixture of the desired product and 3-methylthiopene-2-carbaldehyde in 4:1 ratio as a colorless liquid.

Preparation of Intermediate 350b 3-(Ethoxycarbonyl)-4-(4-methylthien-2-yl)but-3-enoic Acid

Sodium ethylate (71 g, 1.05 mol) was added under vigorous stirring to a solution of 4-methylthiopene-2-carbaldehyde (88 g, 80% purity, 0.56 mol) and diethyl succinate (183 g, 1.05 mol) in ethanol (1 L). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 1 L of a saturated aqueous solution of NaHCO₃, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give the desired product 61 g (0.24 mol, 43%) as yellow crystals.

Preparation of Intermediate 350c Ethyl 4-(Acetyloxy)-3-methyl-1-benzothiophene-6-carboxylate

Sodium acetate (90 g, 1.08 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(4-methylthien-2-yl)but-3-enoic acid (61 g, 0.24 mol) in 700 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO₃ and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 38.5 g (140 mmol, 58%) as a solid.

Preparation of Intermediate 350d Ethyl 4-Hydroxy-3-methyl-1-benzothiophene-6-carboxylate

Ethyl 4-(acetyloxy)-3-methyl-1-benzothiophene-6-carboxylate was dissolved in absolute ethanol (500 mL). Potassium carbonate (35 g, 0.25 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (2:1) to give the desired product 19.5 g (82 mmol, 60%) as a cream solid. ¹H NMR (DMSO-D6): δ ppm 1.35 (t,3H), 2.60 (s, 3H), 4.20 (qt, 2H), 7.29 (m, 1H), 7.35 (s, 1H), 7.95 (s, 1H); MS (APCI, pos): 237.1.

Example 350 3-Methyl-N-(5-methylpyridin-2-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzothiophene-6-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.31 (s, 3 H) 2.44 (s, 3 H) 3.06 (s, 3 H) 7.00-7.16 (m, 2 H) 7.21 (d, J=0.94 Hz, 1 H) 7.53 (d, J=1.32 Hz, 1 H) 7.60 (dd, J=8.57, 2.17 Hz, 1 H) 7.85-7.99 (m, 2 H) 8.06 (s, 1 H) 8.29 (d, J=8.48 Hz, 1 H) 8.35 (d, J=1.32 Hz, 1 H) 9.27 (s, 1H); LCMS m/z 453.0 (M+H)⁺.

Example 351 3-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-4-[4-(methylsulfonyl)-phenoxy]-1-benzothiophene-6-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.44 (d, J=0.94 Hz, 3 H) 3.05 (s, 3 H) 3.79 (s, 3 H) 6.87 (d, J=2.45 Hz, 1 H) 7.01-7.16 (m, 2 H) 7.19 (d, J=1.13 Hz, 1 H) 7.29 (d, J=2.26 Hz, 1 H) 7.56 (d, J=1.51 Hz, 1 H) 7.80-7.98 (m, 2 H) 8.36 (d, J=1.51 Hz, 1 H) 9.87 (s, 1 H); LCMS m/z 442.0 (M+H)⁺.

Examples 352 and 353 were prepared in a similar manner as described for Example 276, via three steps, from ethyl 4-hydroxy-3-methyl-1-benzothiophene-6-carboxylate (350d).

Example 352 4-{4-[(Dimethylamino)carbonyl]phenoxy}-3-methyl-N-(1-methyl-1H-pyrazol-3-yl)-1-benzothiophene-6-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.47 (s, 3 H) 3.06 (s, 6 H) 3.70 (s, 3 H) 6.80 (d, J=2.07 Hz, 1 H) 6.94 (d, J=8.67 Hz, 2 H) 7.13 (d, J=1.13 Hz, 1 H) 7.27 (d, J=2.07 Hz, 1 H) 7.34-7.50 (m, 3 H) 8.16 (d, J=1.13 Hz, 1 H) 9.33 (s, 1 H); LCMS m/z 435.0 (M+H)⁺.

Example 353 4-{4-[(Dimethylamino)carbonyl]phenoxy}-3-methyl-N-(5-methylpyridin-2-yl)-1-benzothiophene-6-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.31 (s, 3 H) 2.49 (s, 3 H) 3.08 (br.s, 6 H) 6.93-7.02 (m, 2 H) 7.18 (d, J=1.13 Hz, 1 H) 7.35-7.46 (m, 3 H) 7.62 (dd, J=8.48, 2.26 Hz, 1 H) 8.08 (d, J=2.26 Hz, 1 H) 8.22 (d, J=8.48 Hz, 1 H) 8.26 (d, J=1.13 Hz, 1 H) 9.09 (s, 1 H); LCMS m/z 446.0 (M+H)⁺.

Example 354 3-Methyl-4-[(1S)-1-methyl-2-phenylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-1-benzothiophene-6-carboxamide

The title compound was prepared in a similar manner as described for Example 328, via two steps, from ethyl 4-hydroxy-3-methyl-1-benzothiophene-6-carboxylate (350d). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (d, J=6.03 Hz, 3 H) 2.58 (d, J=1.13 Hz, 3 H) 2.96 (dd, J=13.75, 6.22 Hz,1 H) 3.17 (dd, J=13.75, 6.03 Hz, 1 H) 3.77 (s, 3 H) 4.81-5.01 (m, 1 H) 6.86 (d, J=2.26 Hz, 1 H) 7.00 (d, J=1.13 Hz, 1 H) 7.13-7.24 (m, 1 H) 7.25-7.37 (m, 6 H) 7.84 (d, J=1.32 Hz, 1 H) 8.99 (s, 1 H); LCMS m/z 406.0 (M+H)⁺.

Example 355 4-(4-Methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide

Dimethylaluminum chloride (15.5 mmol, 15.5 ml of 1M in hexanes) was added to a solution of 2-amino-5-picoline (1.67g, 15.5 mmol) in dichloroethane (10 ml) at 0 C. The mixture was allowed to warm to room temperature, held 30 minutes at room temperature, then recooled to 0° C. and treated with 4-(4-methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid ethyl ester (0.58 g, crude product from previous step) in dichloroethane (5 ml). The mixture is allowed to warm to room temperature and held at room temperature for 8 h. The reaction was quenched by the drop wise addition of MeOH (2 mL) at 0 C, followed by 1M aqueous pH6 phosphate buffer (10 ml), then ethyl acetate (50 ml). Separation of the organic layer followed by evaporation yielded crude product (1.1 g). This was purified by silica gel chromatography (0-20% MeOH/CHCl₃) to yield 0.35 g (59%) of 4-(4-methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.85(s, 1H), 8.69 (s, 1H), 8.22(d, J=8.8, 2H), 8.10 (d, J=8.6, 1H), 8.03 (d, J=5.5, 1H), 7.94 (d, J=8.8, 2H), 7.76 (d, J=1.3, 1H), 7.67 (dd, J=9.0, 2.0, 1H), 7.38 (d, J=5.5, 1H), 7.26 (d, J=8.8, 2H), 3.21 (s, 3H0, 2.28 (s, 3H). LRMS for C₂₂H₁₈N₂O₄S₂ m/z 439 (M+H)⁺. Anal. Calcd. for C₂₂H₁₈N₂O₄S₂ C, 60.26;H, 4.14; N, 6.39; Found: C, 60.58; H, 4.23; N, 6.22.

Preparation of Intermediate 355a 3-(Ethoxycarbonyl)-4-thien-2-ylbut-3-enoic acid

Sodium ethylate (41.4 g, 0.61 mol) was added under vigorous stirring to a solution of thiophene-2-carbaldehyde (57 g, 0.51 mol) and diethyl succinate (176 g, 1.01 mol) in ethanol (1 L). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 300 mL of a saturated aqueous solution of NaHCO₃, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give 60 g (0.25 mol, 49%) of 3-(ethoxycarbonyl)-4-thien-2-ylbut-3-enoic acid as a light-brown oil.

Preparation of Intermediate 355b 4-(Acetyloxy)-1-benzothiophene-6-carboxylic acid ethyl ester

Sodium acetate (30 g, 0.36 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-thien-2-ylbut-3-enoic acid (60 g, 0.25 mol) in 250 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO₃ and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture, 3:1 as eluent to give 21 g (79 mmol, 32%) of compound 4-(acetyloxy)-1-benzothiophene-6-carboxylic acid ethyl ester as a gray solid.

Preparation of Intermediate 355c 4-Hydroxy-1-benzothiophene-6-carboxylic acid ethyl ester

4-(Acetyloxy)-1-benzothiophene-6-carboxylate was dissolved in absolute ethanol (200 mL). Potassium carbonate (14 g, 0.1 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture, 2:1 as eluent to give 6.5 g (29 mmol, 37%) of ethyl 4-hydroxy-1-benzothiophene-6-carboxylate as a cream-colored solid.

Preparation of Intermediate 355d 4-(4-Methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid ethyl ester

4-Hydroxy-1-benzothiophene-6-carboxylic acid ethyl ester (300 mg, 1.35 mmol) in dimethylacetamide (6.8 ml) was treated with cesium carbonate (0.44 g, 1.35 mmol) and 4-fluorophenyl methane sulfonamide (0.23 g, 1.35 mmol) and heated at 100 C for 3 h. The reaction was diluted with EtOAc (50 ml) and washed with 3×10 saturated aqueous sodium bicarbonate. Evaporation yielded 0.58 g of 4-(4-Methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid ethyl ester. LRMS for C₁₈H₁₇O₆S₂ m/z 377 (M+H)⁺.

Example 356 4-(4-(Methylsulfonyl)phenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzo-[b]-thiophene-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxybenzo[b]thiophene-6-carboxylate (0.275 g, 1.24 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (0.22 g, 1.26 mmol) in DMF (5 ML). The mixture was stirred at 120° C. for 8 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.18 g, 1.85 mmol) and HATU (0.7 g, 1.85 mmol) were added. The reaction mixture was stirred at 50° C. for one hour and then filtered. Purification by HPLC gave a solid (127 mg, 24% yield) as expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1 H) 8.57-8.63 (m, 1 H) 8.01-8.07 (m, 1 H) 7.94-7.96 (m 2 H) 7.73 (m, 1 H) 7.61 (m, 1 H) 7.38-7.41 (m, 1 H) 7.25-7.27 (m, 2 H) 6.60 (m, 1 H) 3.78 (s, 3 H), 3.22 (s, 3 H). LCMS for C₂₀H₁₇N₃O₄S₂ m/z 428.10 (M+H)⁺.

Example 357 4-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzo[b]thiophene-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxybenzo[b]thiophene-6-carboxylate (0.275 g, 1.24 mmol) and 2,4-difluoro-N,N-dimethylbenzamide (0.234 g, 1.26 mmol) in DMF (5 ML). The mixture was stirred at 150° C. for 10 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.18 g, 1.85 mmol) and HATU (0.7 g, 1.85 mmol) were added. The reaction mixture was stirred at 50° C. for one hour and then filtered. Purification by HPLC gave a solid (200 mg, 38% yield) as expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1 H) 8.59 (m, 1 H) 8.00 (m, 1 H)) 7.61-7.68 (m, 2 H) 7.39-7.43 (m, 2 H) 7.08-7.11 (m, 1 H) 6.92-6.95 (m, 1 H) 6.60 (s, 1 H) 3.79 (s, 3 H) 3.00 (s, 3 H) 2.88 (m, 3 H). LCMS for C₂₂H₁₉FN₄O₃S m/z 439.10 (M+H)⁺.

Example 358 4-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-N-(5-methylpyridin-2-yl)benzo[b]thiophene-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxybenzo[b]thiophene-6-carboxylate (0.275 g, 1.24 mmol) and 2,4-difluoro-N,N-dimethylbenzamide (0.286 g, 1.55 mmol) in DMF (5 ML). The mixture was stirred at 150° C. for 8 hours and then cooled to room temperature. 2-Amino-5-methyl pyridine (0.228 g, 2.11 mmol) and then HATU (0.7 g, 1.85 mmol) were added. The reaction mixture was stirred at 75° C. for four hours and then filtered. Purification by HPLC gave a solid (57 mg, 10% yield) as expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s, 1 H) 8.64 (s, 1 H) 8.22 (m, 1 H) 8.07-8.09 (d, 1 H)) 8.01-8.02 (d, 1 H) 7.69 (m, 1 H) 7.65-7.68 (m, 1 H) 7.39-7.43 (m, 2 H) 7.08-7.11 (m, 1 H) 6.93-6.95 (m, 1 H) 2.99 (s, 3 H) 2.87 (m, 3 H) 2.28 (s, 3 H). LCMS for C₂₄H₂₀FN₃O₃S m/z 450.10 (M+H)⁺.

Example 359 4-(4-Methanesulfonyl-phenoxy)-2-methyl-benzo[b]thiophene-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide

Dimethylaluminum chloride (16.1 mmol, 16.1 ml of 1M in hexanes) is added to a solution of 2-amino-5-picoline (1.74g, 16.1 mmol) in dichloroethane (10 ml) at 0 C. The mixture was allowed to warm to room temperature over a period of 1 h, then recooled to 0 C and treated with 4-(4-methanesulfonyl-phenoxy)-2-methyl-benzo[b]thiophene-6-carboxylic acid ethyl ester (0.63 g, crude product from previous step) in dichloroethane (5 ml) at 0 C. The mixture was allowed to warm to room temperature, and held at room temperature for 8 h. The reaction was quenched by the drop wise addition of MeOH (2 ml) at 0 C, followed by 1M aqueous pH6 phosphate buffer (10 ml), then ethyl acetate was added (50 ml). Separation of the organic layer followed by evaporation yields 0.80 g crude product. Purification by silica gel chromatography (0-20% MeOH-CHCl₃) yielded 0.39 g (68%) of product 4-(4-methanesulfonyl-phenoxy)-2-methyl-benzo[b]thiophene-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide. LRMS for C₂₃H₂₀N₂O₄S₂ m/z 453 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.56 (s, 1H), 8.22 (d, J=2.3, 1H), 8.08 (d, J=8.3, 1H), 7.93 (d, J=8.8, 2H), 7.74 (d, J=1.2, 2H), 7.67 (dd, J=8.6, 2.0, 1H), 7.22 (d, J=8.8, 2H), 7.09 (s, 1H), 3.21 (s, 3H), 2.59 (d, J=1.0, 3H), 2.28 (s, 3H). Anal. Calcd. for C₂₃H₂₀N₂O₄S₂: C, 61.04; H, 4.45; N, 6.19; Found: C, 61.01; H, 4.47; N, 5.96.

Preparation of Intermediate 359a 3-(Ethoxycarbonyl)-4-(5-methyl-2-thienyl)but-3-enoic acid

Sodium ethylate (6.5 g, 95 mmol) was added under vigorous stirring to a solution of 5-methylthiophene-2-carbaldehyde (10 g, 79 mmol) and diethyl succinate (27.6 g, 158 mmol) in ethanol (300 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 200 mL of 10% HCl and 300 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 200 mL of a saturated aqueous solution of NaHCO₃, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 400 mL of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions containing the target product were collected and evaporated in vacuum to give 12.3 g (48 mmol, 61%) of 3-(ethoxycarbonyl)-4-(5-methyl-2-thienyl)but-3-enoic acid as a light-brown oil.

Preparation of Intermediate 359b 4-(Acetyloxy)-2-methyl-1-benzothiophene-6-carboxylic acid ethyl ester

Sodium acetate (10 g, 120 mmol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-2-thienyl)but-3-enoic acid (12.3 g, 48 mmol) in 100 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 250 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a saturated aqueous solution of NaHCO₃ and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture, 3:1 as eluent to give 8.2 g (29 mmol, 61%) of 4-(acetyloxy)-2-methyl-1-benzothiophene-6-carboxylic acid ethyl ester as a yellow solid.

Preparation of Intermediate 359c 4-Hydroxy-2-methyl-1-benzothiophene-6-carboxylic acid ethyl ester

Ethyl 4-(acetyloxy)-2-methyl-1-benzothiophene-6-carboxylate was dissolved in absolute ethanol (200 mL). Potassium carbonate (7 g, 50 mmol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture, 2:1 as eluent to give 5.5 g (23 mmol, 79%) of 4-Hydroxy-2-methyl-1-benzothiophene-6-carboxylate ethyl ester as a cream solid.

Preparation of Intermediate 359d 4-(4-Methanesulfonyl-phenoxy)-2-methyl-benzo[b]thiophene-6-carboxylic acid ethyl ester

4-Hydroxy-2-methyl-1-benzothiophene-6-carboxylic acid ethyl ester (300 mg, 1.27 mmol) in dimethylacetamide (6.36 ml, 0.2 M) was treated with cesium carbonate (0.41 g, 1.27 mmol) and 4-fluorophenylmethane sulfonamide (0.22 g, 1.27 mmol) and heated at 100 C for 3h. The reaction was then diluted with EtOAc (50 ml), and washed with 3×10 ml of saturated aqueous sodium bicarbonate. Evaporation yields 0.63 g of 4-(4-methanesulfonyl-phenoxy)-2-m3thyl-benzo[b]thiophene-6-carboxylic acid ethyl ester. LRMS for C₁₉H₁₉O₅S₂ m/z 391 (M+H)⁺.

Example 360 4-(4-(Methylsulfonyl)phenoxy)-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzo[b]thiophene-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxybenzo[b]thiophene-6-carboxylate (0.293 g, 1.24 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (0.22 g, 1.26 mmol) in DMF (5 ML). The mixture was stirred at 120° C. for 8 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.18 g, 1.85 mmol) and HATU (0.7 g, 1.85 mmol) were added. The reaction mixture was stirred at 50° C. for one hour and then filtered. Purification by HPLC gave a solid (107 mg, 20% yield) as expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1 H) 8.51 (s, 1 H) 7.92-7.94 (m, 2 H) 7.71 (m, 1 H) 7.60-7.61 (m, 1 H) 7.20-7.23 (m, 2 H) 7.08-7.10 (m, 1 H) 6.58-6.59 (m, 1 H) 3.78 (s, 3 H), 3.21 (s, 3 H), 2.58 (m, 3 H). LCMS for C₂₁H₁₉N₃O₄S₂ m/z 442.10 (M+H)⁺.

Example 361 4-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-2-methyl-N-(5-methylpyridin-2-yl)benzo[b]thiophene-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxy-2-methylbenzo[b]thiophene-6-carboxylate (0.275 g, 1.16 mmol) and 2,4-difluoro-N,N-dimethylbenzamide (0.269 g, 1.45 mmol) in DMF (5 ML). The mixture was stirred at 150° C. for 8 hours and then cooled to room temperature. 2-Amino-5-methyl pyridine (0.214 g, 2 mmol) and HATU (0.67 g, 1.75 mmol) were added. The reaction mixture was stirred at 75° C. for four hours and then filtered. Purification by HPLC gave a solid (92 mg, 17% yield) as expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1 H) 8.52 (s, 1 H) 8.21 (m, 1 H) 8.06-8.08 (d, 1 H) 7.68 (m, 1 H) 7.64-7.67 (m, 1 H) 7.37-7.41 (t, 1 H) 7.12 (s, 1 H) 7.02-7.06 (m, 1 H) 6.87-6.90 (m, 1 H) 2.99 (s, 3 H) 2.87 (s, 3 H) 2.59-2.60 (m, 3 H) 2.28 (s, 1 H). LCMS for C₂₅H₂₂FN₃O₃S m/z 464.10 (M+H)⁺.

Example 362 4-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzo[b]thiophene-6-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 4-hydroxy-2-methylbenzo[b]thiophene-6-carboxylate (0.275 g, 1.16 mmol) and 2,4-difluoro-N,N-dimethylbenzamide (0.269 g, 1.45 mmol) in DMF (5 ML). The mixture was stirred at 150° C. for 8 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.19 g, 1.98 mmol) and HATU (0.664 g, 1.75 mmol) were added. The reaction mixture was stirred at 80° C. for one hour and then filtered. Purification by HPLC gave a solid (100 mg, 19% yield) as expected product. ¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1 H) 7.54 (m, 1 H) 7.48 (m, 1 H) 7.34-7.38 (t, 1 H) 7.00 (s, 1 H) 6.82-6.89 (m, 2 H) 6.59-6.60 (m, 1 H) 3.81 (s, 3 H) 3.09 (s, 3 H) 2.97 (m, 3 H) 2.58 (m, 3 H). LCMS for C₂₃H₂₁FN₄O₃S m/z 453.10 (M+H)⁺.

Example 363 7-(4-Methanesulfonyl-phenoxy)-benzo[b]thiophene-5-carboxylic acid(5-methyl-pyridin-2-yl)-amide

7-Hydroxy-benzo[b]thiophene-5-carboxylic acid ethyl ester (295 mg, 1.33 mmol) in dimethylacetamide (6.5 ml) was treated with cesium carbonate (0.43 g, 1.33 mmol), and 4-fluorophenylmethane sulfonamide (0.23 g, 1.33 mmol), and heated at 100 C for 3 h. The mixture was diluted with EtOAc (50 ml) and washed with saturated aqueous NaHCO₃ (3×10 ml). Evaporation yields 0.56 g of 4-(4-methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid ethyl ester (6). LRMS for C₁₈H₁₇S₂O₅ m/z 377 (M+H)⁺. Dimethylaluminum chloride (7.5 mmol, 7.5 ml of 1M in hexanes) was added to a solution of 2-amino-3-picoline (0.81 g, 7.50 mmol) in dichloroethane (10 mL) at 0 C. The mixture was allowed to warm to room temperature, held 30 minutes at room temperature, then recooled to 0 C and treated with 4-(4-methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid ethyl ester (0.56 g, crude material from previous step) in dichloroethane (5 ml). The mixture was allowed to warm to room temperature and held at room temperature for 8 h. The reaction was quenched by the drop wise addition of methanol (2 ml) at 0 C, followed by addition of 1M aqueous pH6 phosphate buffer (10 ml), then ethyl acetate (50 ml). Separation of the organic layer followed by evaporation yields the crude product (0.89 g). This was purified on a silica gel chromatography column using a 0-20% MeOH/CHCl₃ gradient to yield 0.26 g (45%) of product 7-(4-Methanesulfonyl-phenoxy)-benzo[b]thiophene-5-carboxylic acid (5-methyl-pyridin-2-yl)-amide (7). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1H), 8.55 (d, J=1.3, 1H), 8.22 (d, J=1.8, 1H), 8.09 (d, J=8.6, 1H), 7.96 (dt, J=8.8, 2.0, 2H), 7.95 (d, J=5.8, 1H), 7.77 (d, J=1.0, 1H), 7.69 (d, J=5.3, 1H), 7.67 (dd, J=8.8, 2.3, 1H), 7.32 (dt, J=8.8, 2.0, 2H), 3.23 (s, 3H), 2.28 (s, 3H). LRMS for C₂₂H₁₈N₂O₄S₂ m/z 439 (M+H)⁺. Anal. Calcd. for C₂₂H₁₈N₂O₄S₂C, 60.26; H, 4.14; N, 6.39; Found: C, 60.13; H, 4.08; N, 6.32.

Preparation of Intermediate 363a 3-(Ethoxycarbonyl)-4-(2-thienyl)but-3-enoic acid

Sodium ethylate (36.3 g, 0.53 mol) was added under vigorous stirring to a solution of 3-thiophenecarboxaldehyde (50 g, 0.44 mol) and diethyl succinate (116 g, 0.66 mol) in ethanol (1 L). The reaction mixture was refluxed for 8 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 500 mL of a saturated aqueous solution of NaHCO₃, and aqueous layer shaken. The was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm; hexane/ethyl acetate mixture, 1:1). Fractions with the target product were collected and evaporated in vacuum to give 61 g (0.25 mol, 57%) of 3-(ethoxycarbonyl)-4-(2-thienyl)but-3-enoic acid as a light-brown oil.

Preparation of Intermediate 363b Ethyl 7-acetoxy-1-benzothiophene-5-carboxylate

Sodium acetate (40 g, 0.48 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(2-thienyl)but-3-enoic acid (61 g, 0.25 mol) in 250 mL of acetic anhydride. The reaction mixture was refluxed for 2 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 200 mL of dichloromethane. The combined solutions were washed by 200 mL of a saturated aqueous solution of NaHCO₃ and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 3:1 as eluent to give 31 g (0.12 mol, 46%) of ethyl 7-acetoxy-1-benzothiophene-5-carboxylate as a yellow solid.

Preparation of Intermediate 363c Ethyl 7-hydroxy-1-benzothiophene-5-carboxylate

Ethyl 7-acetoxy-1-benzothiophene-5-carboxylate was dissolved in absolute ethanol (500 mL). Potassium carbonate (21 g, 0.15 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 200 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (200×150 mm; hexane/ethyl acetate mixture, 2:1) to give 16.5 g (63 mmol, 63%) of compound ethyl 7-hydroxy-1-benzothiophene-5-carboxylate as a red-brown solid. LRMS for C₁₁H₁₁SO₃ m/z 223 (M+H)⁺.

Example 364 7-(4-(Methylsulfonyl)phenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzo-[b]-thiophene-5-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 7-hydroxybenzo[b]thiophene-5-carboxylate (0.275 g, 1.24 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (0.22 g, 1.26 mmol) in DMF (5 ML). The mixture was stirred at 120° C. for 8 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.21 g, 2.17 mmol) and then HATU (0.71 g, 1.87 mmol) were added. The reaction mixture was stirred at 50° C. for one hour and then filtered. Purification by HPLC gave a solid (6 mg, 1% yield) as expected product. ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1 H) 7.96-7.99 (m, 2 H) 7.73-7.76 (m, 1 H) 7.58-7.61 (m, 2 H) 7.53 (s, 1 H) 7.23-7.28 (m, 2 H) 6.60 (s, 1 H) 3.84 (s, 3 H) 3.13 (s, 3 H). LCMS for C₂₀H₁₇N₃O₄S₂ m/z 428.10 (M+H⁺).

Example 365 7-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-N-(5-methylpyridin-2-yl)benzo[b]thiophene-5-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 7-hydroxybenzo[b]thiophene-5-carboxylate (0.275 g, 1.24 mmol) and 2,4-difluoro-N,N-dimethylbenzamide (0.286 g, 1.55 mmol) in DMF (5 ML). The mixture was stirred at 150° C. for 8 hours and then cooled to room temperature. 2-Amino-5-methyl pyridine (0.228 g, 2.11 mmol) and then HATU (0.7 g, 1.85 mmol) were added. The reaction mixture was stirred at 75° C. for four hours and then filtered. Purification by HPLC gave a solid (56 mg, 10% yield) as expected product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1 H) 8.51 (m, 1 H) 8.23 (s, 1 H) 8.07-8.09 (d, 1 H)) 7.93-7.94 (m, 1 H) 7.67-7.70 (m, 3 H) 7.41-7.46 (t, 1 H) 7.15-7.17 (m, 1 H) 7.00-7.03 (m, 1 H) 3.00 (s, 3 H) 2.88 (m, 3 H) 2.29 (s, 3 H). LCMS for C₂₄H₂₀FN₃O₃S m/z 450.10 (M+H)⁺.

Example 366 7-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzo[b]thiophene-5-carboxamide

Cs₂CO₃ (0.806 g, 2.47 mmol) was added to a solution of ethyl 7-hydroxybenzo[b]thiophene-5-carboxylate (0.275 g, 1.24 mmol) and 2,4-difluoro-N,N-dimethylbenzamide (0.286 g, 1.55 mmol) in DMF (5 ML). The mixture was stirred at 150° C. for 8 hours and then cooled to room temperature. 1-Methyl-1H-pyrazol-3-amine (0.21 g, 2.17 mmol) and then HATU (0.71 g, 1.87 mmol) were added. The reaction mixture was stirred at 50° C. for one hour and then filtered. Purification by HPLC gave a solid (100 mg, 19% yield) as expected product. DMSO-d₆) δ 10.96 (s, 1 H) 8.46 (m, 1 H) 7.91-7.93 (d, 1 H)) 7.67 (m, 1 H) 7.65-7.66 (m, 1 H) 7.60-7.61 (m, 1 H) 7.41-7.45 (t, 1 H) 7.14-7.17 (m, 1 H) 6.99-7.01 (m, 1 H) 6.59 (m, 1 H) 3.78 (s, 3 H) 3.00 (s, 3 H) 2.88 (m, 3 H).

Example 367 N-(5-methylpyridin-2-yl)-7-[4-(methylsulfonyl)phenoxy]-1,3-benzoxazole-5-carboxamide

The title compound was prepared in a similar manner as described for Example 252, via two steps, from methyl 7-hydroxybenzo[d]oxazole-5-carboxylate (367e). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.30 (s, 3 H) 3.06 (s, 3 H) 7.12-7.22 (m, 2 H) 7.58 (dd, J=8.48, 2.26 Hz, 1 H) 7.80 (d, J=1.32 Hz, 1 H) 7.88-7.98 (m, 2 H) 8.09 (d, J=2.26 Hz, 1 H) 8.17 (s, 1 H) 8.23 (d, J=8.48 Hz, 1 H) 8.26 (d, J=1.32 Hz, 1 H); LCMS m/z 424.40 (M+H)⁺.

Preparation of Intermediate 367a 3,4-Dihydroxy-5-nitrobenzaldehyde

To a vigorously stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (47.0 g, 238 mmol) in EtOAc (450 mL) at room temperature, anhydrous aluminum chloride (38.1 g, 286 mmol) was added in one portion. Then pyridine (77 mL, 954 mmol) was added drop wise at 45-50° C. for 30 min. The reaction mixture was refluxed for 2 h and allowed to cool down to 60° C. The reaction mixture was carefully poured into ice/concentrated HCl mixture (265 mL). After stirring at 50° C. for 1 h, the reaction mixture was cooled to 0° C. The formed precipitate was separated by filtration, washed with water, and vacuum-dried to afford the desired compound (29.4 g, 161 mmol, 67.3% yield).

Preparation of Intermediate 367b 3,4-Dihydroxy-5-nitrobenzoic Acid

A solution of sodium chlorite (47.6 g, 526 mmol) in water (350 mL) was added drop wise to a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (68.8 g, 376 mmol) and sodium dihydrogen phosphate (45.1 g, 376 mmol) in DMSO/H₂O mixture (375 mL/150 mL) at room temperature for 1.5 h. The reaction mixture was stirred at room temperature for 1 h and poured into a separatory funnel containing a 5% solution NaHCO₃ (500 mL). The product was extracted with dichloromethane (3×100 mL). The water layer was acidified with concentrated HCl to pH˜1 and extracted with ether (3×250 mL). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, and evaporated to afford the desired acid (70.3 g, 353 mmol, 94% yield).

Preparation of Intermediate 367c Methyl 3,4-Dihydroxy-5-nitrobenzoate

Thionyl chloride (6.07 mL, 83 mmol) was added drop wise to a stirred solution of 3,4-dihydroxy-5-nitrobenzoic acid (14.4 g, 72.3 mmol) in MeOH (70 mL) at room temperature for 1 h. The reaction mixture was refluxed for 3 h and concentrated. The residue was recrystallized from water and vacuum-dried to afford the desired ester (11.0 g, 51.6 mmol, 71.4% yield).

Preparation of Intermediate 367d Methyl 3-Amino-4,5-dihydroxybenzoate Hydrochloride

To a stirred solution of methyl 3,4-dihydroxy-5-nitrobenzoate (11.9 g, 55.8 mmol) in EtOH (200 mL), 4M HCl in dioxane (13.96 mL, 55.8 mmol) and 10% palladium on carbon (4.0 g, 3.76 mmol) were added. The reaction mixture was hydrogenated at atmospheric pressure of H₂ for 3 h (TLC-monitoring). The resulting mixture was filtered and concentrated. The residue was triturated with ether (100 mL). The precipitate was filtered off and vacuum-dried to afford amine product as the hydrochloride salt (12.0 g, 54.6 mmol, 98% yield).

Preparation of Intermediate 367e: Methyl 7-Hydroxy-1,3-benzoxazole-5-carboxylate

To stirred triethyl orthoformate (35.0 mL, 210 mmol) was added methyl 3-amino-4,5-dihydroxybenzoate hydrochloride (6.30 g, 28.7 mmol). The stirred suspension was refluxed for 20 min (until a clear solution formed), cooled to room temperature, and poured into hexane (200 mL). The formed precipitate was separated by filtration and vacuum-dried to afford the desired benzoxazole (4.26 g, 22.05 mmol, 77% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (br. s, 1H), 8.79 (s, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.50 (d, J=1.3 Hz, 1H), 3.86 (s, 3H).

Examples 368 and 369 were prepared in a similar manner as described for Example 252, via two steps, from methyl 7-hydroxy-2-methylbenzo[d]oxazole-5-carboxylate (368e).

Preparation of Intermediate 368a 3,4-Dihydroxy-5-nitrobenzaldehyde

To a vigorously stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (47.0 g, 238 mmol) in EtOAc (450 mL) at room temperature, anhydrous aluminum chloride (38.1 g, 286 mmol) was added in one portion. Then pyridine (77 mL, 954 mmol) was added drop wise at 45-50° C. for 30 min. The reaction mixture was refluxed for 2 h and allowed to cool down to 60° C. The reaction mixture was carefully poured into ice/concentrated HCl mixture (265 mL). After stirring at 50° C. for 1 h, the reaction mixture was cooled to 0° C. The formed precipitate was separated by filtration, washed with water, and vacuum-dried to afford the desired compound (29.4 g, 161 mmol, 67.3% yield).

Preparation of Intermediate 368b 3,4-Dihydroxy-5-nitrobenzoic Acid

A solution of sodium chlorite (47.6 g, 526 mmol) in water (350 mL) was added drop wise to a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (68.8 g, 376 mmol) and sodium dihydrogen phosphate (45.1 g, 376 mmol) in DMSO/H₂O mixture (375 mL/150 mL) at room temperature over 1.5 h. The reaction mixture was stirred at room temperature for 1 h and poured into a separatory funnel containing a 5% solution NaHCO₃ (500 mL). The product was extracted with dichloromethane (3×100 mL). The water layer was acidified with concentrated HCl to pH˜1 and extracted with ether (3×250 mL). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, and evaporated to afford the desired acid (70.3 g, 353 mmol, 94% yield).

Preparation of Intermediate 368c Methyl 3,4-Dihydroxy-5-nitrobenzoate

Thionyl chloride (6.07 mL, 83 mmol) was added drop wise to a stirred solution of 3,4-dihydroxy-5-nitrobenzoic acid (14.4 g, 72.3 mmol) in MeOH (70 mL) at room temperature for 1 h. The reaction mixture was refluxed for 3 h and concentrated. The residue was recrystallized from water and vacuum-dried to afford the desired ester (11.0 g, 51.6 mmol, 71.4% yield).

Preparation of Intermediate 368d Methyl 3-amino-4,5-dihydroxybenzoate hydrochloride

To a stirred solution of methyl 3,4-dihydroxy-5-nitrobenzoate (11.9 g, 55.8 mmol) in EtOH (200 mL) was added 4M HCl in dioxane (13.96 mL, 55.8 mmol) and 10% palladium on carbon (4.0 g, 3.76 mmol). The reaction mixture was hydrogenated at atmospheric pressure of H₂ for 3 h (TLC-monitoring). The resulting mixture was filtered and concentrated. The residue was triturated with ether (100 mL). The precipitate was filtered off and vacuum-dried to afford amine product as the hydrochloride salt (12.0 g, 54.6 mmol, 98% yield).

Preparation of Intermediate 368e Methyl 7-hydroxy-2-methyl-1,3-benzoxazole-5-carboxylate

To stirred triethyl orthoacetate (35.0 mL, 190 mmol) was added methyl 3-amino-4,5-dihydroxybenzoate hydrochloride (6.00 g, 27.3 mmol). The stirred suspension was refluxed for 20 min and cooled to room temperature. The reaction mixture was poured into hexane (200 mL). The formed precipitate was separated by filtration and vacuum-dried to afford the desired benzoxazole (4.98 g, 24.04 mmol, 88% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (br. s, 1H), 7.66 (d, J=1.4 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H), 3.85 (s, 3H), 2.62 (s, 3H).

Example 368 2-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-7-[4-(methylsulfonyl)-phenoxy]-1,3-benzoxazole-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.65 (s, 3 H) 3.07 (s, 3 H) 3.79 (s, 3 H) 6.79 (d, J=2.26 Hz, 1 H) 7.08-7.22 (m, 2 H) 7.29 (d, J=2.26 Hz, 1 H) 7.64 (d, J=1.32 Hz, 1 H) 7.88-7.98 (m, 2 H) 8.01 (d, J=1.32 Hz, 1 H) 8.83 (s, 1 H); LCMS m/z 427.40 (M+H)⁺.

Example 369 2-Methyl-N-(5-methylpyridin-2-yl)-7-[4-(methylsulfonyl)-phenoxy]-1,3-benzoxazole-5-carboxamide

¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.32 (s, 3 H) 2.66 (s, 3 H) 3.07 (s, 3 H) 7.11-7.22 (m, 2 H) 7.60 (dd, J=8.48, 2.26 Hz, 1 H) 7.70 (d, J=1.51 Hz, 1 H) 7.87-8.01 (m, 2 H) 8.08 (d, J=2.26 Hz, 1 H) 8.12 (d, J=1.51 Hz, 1 H) 8.28 (d, J=8.48 Hz, 1 H) 9.29 (s, 1 H); LCMS m/z 438.40 (M+H)⁺.

Example 370 7-{4-[(Dimethylamino)carbonyl]phenoxy}-2-methyl-N-(5-methylpyridin-2-yl)-1,3-benzoxazole-5-carboxamide

The title compound was prepared in a similar manner as described for Example 276, via three steps, from methyl 7-hydroxy-2-methylbenzo[d]oxazole-5-carboxylate (368e). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.33 (s, 3 H) 2.65-2.67 (s, 3 H) 3.03 (s, 3 H) 3.11 (s, 3 H) 7.05 (d, J=8.67 Hz, 2 H) 7.41 (d, J=8.67 Hz, 2 H) 7.53 (d, J=1.32 Hz, 1 H) 7.65 (dd, J=8.57, 2.17 Hz, 1 H) 7.99 (d, J=1.32 Hz, 1 H) 8.12 (d, J=2.17 Hz, 1 H) 8.17 (d, J=8.57 Hz, 1 H) 9.04 (s, 1 H); LCMS m/z 431.40 (M+H)⁺.

Example 371 N-(5-Methylpyridin-2-yl)-4-[4-(methylsulfonyl)phenoxy]-1,3-benzothiazole-6-carboxamide

The title compound was prepared in a similar manner as described for Example 252, via two steps, from methyl 4-hydroxybenzo[d]thiazole-6-carboxylate (371e). ¹H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.32 (s, 3 H) 3.06 (s, 3 H) 7.07-7.22 (m, 2 H) 7.59 (dd, J=8.48, 2.45 Hz, 1 H) 7.73 (d, J=1.51 Hz, 1 H) 7.86-8.01 (m, 2 H) 8.11 (s, 1 H) 8.24 (d, J=8.48 Hz, 1 H) 8.44 (d, J=1.70 Hz, 1 H) 8.70 (s, 1 H) 9.11 (s, 1 H); LCMS m/z 440.20 (M+H)⁺.

Preparation of Intermediate 371a Methyl 3-methoxy-4-nitrobenzoate

To a mixture of 3-hydroxy-4-nitrobenzoic acid (203 g, 1.109 mol) and K₂CO₃ (345 g, 2.496 mol) in DMF (3000 mL) was added drop wise CH₃I (400 g, 2.817 mol) at ambient temperature. The mixture was stirred at ambient temperature for 13 h. TLC (EtOAc: Petroleum ether 1:4) indicated the reaction was complete. Most of the solvent was removed under reduced pressure and the residue was diluted with water (2 L). Then the mixture was extracted with EtOAc (2 L×3). The combined organic layers were washed with water (1L×3), dried over Na₂SO₄ and concentrated under reduced pressure to yield the desired ester (172 g, 73.5%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.848-7.827 (d, 2H), 7.759 (s, 1H), 7.705-7.681 (d, 1H), 4.018 (s, 3H), 3.969 (s, 3H).

Preparation of Intermediate 371b Methyl 4-amino-3-methoxybenzoate

To a solution of methyl 3-methoxy-4-nitrobenzoate (172 g, 0.815 mol) in methanol (2 L) was added Raney Ni (60 g) in one portion. The resulting mixture was stirred at ambient temperature under H₂ for 24 h. TLC

(EtOAc: Petroleum ether 1:3) indicated the reaction was complete. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with methanol (100 mL×5). The filtrate was concentrated in vacuum to afford the desired amine (128 g, 86.7%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.383-7.349 (dd, 1H), 7.268 (d, 1H), 6.633-6.605 (d, 1H), 5.617 (s, 2H), 3.782 (s, 3H), 3.740 (s, 3H).

Preparation of Intermediate 371c: Methyl 2-amino-4-methoxy-1,3-benzothiazole-6-carboxylate

To a solution of methyl 4-amino-3-methoxybenzoate (307 g, 1.696 mol) in anhydrous methanol (4 L) was added an intimated mixture of KSCN (1640 g, 16.9 mol) and anhydrous CuSO₄ (1350 g, 8.44 mol) in one portion. The mixture was heated to reflux for 4 h. TLC (EtOAc/Petroleum ether 1:4) showed the reaction was complete. The mixture was filtered and the filtrate was diluted with water. The solution was heated to boiling until a slightly clear solution formed. The mixture was cooled to ambient temperature and left standing for 1 day. A dark yellow solid was formed, which was collected by filtration to afford the desired product (338 g, 84%) as a dark yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 9.000-8.200 (br, 2H), 8.052 (s, 1H), 7.435 (s, 1H), 3.927 (s, 3H), 3.827 (s, 3H).

Preparation of Intermediate 371d: Methyl 4-methoxy-1,3-benzothiazole-6-carboxylate

To a stirred solution of methyl 2-amino-4-methoxy-1,3-benzothiazole-6-carboxylate (100 g, 0.42 mol) in DMF (1 L) was added drop wise isoamyl nitrite (108 g, 0.92 mol) at 65° C. Then the resulting mixture was stirred at 65° C. for 20 min. TLC (EtOAc/Petroleum ether 1:4) showed the reaction was complete. After cooling to ambient temperature, the mixture was poured into ice water (1 L). The resulting mixture was extracted with EtOAc (1 L×3). The combined organic layers were washed with water (1 L×2), dried over Na₂SO₄ and concentrated in vacuum. The residue was purified by chromatography (silica gel, EtOAc/Petroleum ether 1:50 to 1:10) to afford the product (22 g, 23%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 9.050 (s, 1H), 8.285-8.281 (d, 1H), 7.592-7.587 (d, 1H), 4.110 (s, 3H), 3.965 (s, 3H).

Preparation of Intermediate 371e: Methyl 4-hydroxy-1,3-benzothiazole-6-carboxylate

To a stirred solution of methyl 4-methoxy-1,3-benzothiazole-6-carboxylate (20.0 g, 0.0897 mol) in anhydrous CH₂Cl₂ (300 mL) was added drop wise BBr₃ (112.5 g, 0.448 mol) at -78° C. Then the resulting mixture was stirred at −78° C. for 3 hours and allowed to warm to room temperature overnight. TLC (EtOAc/Petroleum ether 1:4) showed the reaction was complete. The reaction mixture was concentrated in vacuum and methanol (100 mL) was added drop wise to the residue. Then the mixture was concentrated again in vacuum. The residue was washed with water and recrystallized from methanol to afford the desired product (12 g, 64%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 10.671 (s, 1H), 9.437 (s, 1H), 8.252-8.248 (s, 1H), 7.488-7.484 (s, 1H), 3.898 (s, 3H).

Example 372 4-[4-(Methylsulfonyl)phenoxy]-N-pyridin-2-yl-1,3-benzothiazole-6-carboxamide

The title compound was prepared in a similar manner as described for Example 252, via two steps, from methyl 4-hydroxybenzo[d]thiazole-6-carboxylate (371e). ¹H NMR (400 MHz, CDCl₃): δ 10.000-9.500 (br, 1H), 9.135 (s, 1H), 8.524-8.490 (m, 2H), 8.299 (br, 1H), 7.979-7.896 (m, 3H), 7.786 (s, 1H), 7.212-7.190 (m, 3H), 3.071 (s, 3H). MS (pos): 426.1.

Example 373 6-Methoxy-2-methyl-1H-benzoimidazole-4-carboxylic acid(5-methyl-pyridin-2-yl)-amide

HATU (431 mg, 1.13 mmol) was added to a mixture of 6-methoxy-2-methyl-1H-benzoimidazole-4-carboxylic acid (350 mg, 1.0 mmol), 2-amino-5-picoline (134 mg, 1.24 mmol), and DIEA (0.359mL, 2.06 mmol) in DMF (5 mL) while stirring at room temperature. The resulting mixture was stirred at room temperature under N₂ atmosphere for 16 hours. The mixture was worked up with water and extracted into chloroform; the organic layer was dried over MgSO4, concentrated. The crude product was purified by flash silicagel chromatography (ISCO) eluting with CHCl₃:MeOH (95:5) to gain 85 mg light brown color solid product in 27% yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.68 (s, 1 H) 12.41 (s, 1 H) 8.27 (d, J=8.56 Hz, 1 H) 8.23 (s, 1 H) 7.68 (dd, J=8.56, 1.76 Hz, 1 H) 7.51 (d, J=2.27 Hz, 1 H) 7.23 (d, J=2.27 Hz, 1 H) 3.85 (s, 3 H) 2.61 (s, 3 H) 2.29 (s, 3 H). LRMS for C₁₆H₁₆N₄O₂ m/z 297 (M+H)⁺.

Preparation of Intermediate 373a 1-(1,1-Diethoxy-ethyl)-6-methoxy-2-methyl-1H-benzoimidazole-4-carbonitrile

A mixture of 2,3-diamino-5-methoxybenzonitrile (Ref: U.S. Pat. No. 6,387,938 B1) (1.5 g, 8.7 mmol) in triethyl orthoacetate (16.5 mL, 87.3 mmol) was stirred at 120° C. for 2 hours. The mixture was concentrated to dryness to obtain 2.55 g dark colored oil. The product was carried on to the next step without any further purification. LRMS for C₁₆H₂₁N₃O₃ m/z 304.2 (M+H)⁺.

Preparation of Intermediate 373b 6-Methoxy-2-methyl-1H-benzoimidazole-4-carboxylic acid

A mixture of 1-(1,1-diethoxy-ethyl)-6-methoxy-2-methyl-1H-benzoimidazole-4-carbonitrile (2.5 g, 8.2 mmol), diethylene glycol (5 mL) and 6 N KOH aqueous solution (2.5 mL) was stirred at 150° C. for 16 hours. The mixture was poured into ice water (15 mL) and washed with ethyl acetate (3×100mL). The water layer was then adjusted to pH 7-6 with 6 N HCl aqueous solution. The resulting mixture was washed with EtOAc and the water layer was concentrated down to a volume of 10 mL. The crude product was purified by preparative HPLC to obtain 350 mg of dark colored sticky gum product. ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.98 (bs, 1H) 7.55 (d, J=2.5 Hz, 1H) 7.51 (d, J=2.5 Hz, 1H) 4.20 (bs, 1H) 3.9 (s, 3H) 2.77 (s, 3H). LRMS for C₁₆H₂₁N₃O₃ m/z 205 (M−H)⁻.

Example 374 5-(2-Chloro-benzyloxy)-2,2-dimethyl-chroman-7-carboxylic acid(5-methyl-pyridin-2-yl)-amide and Example 375: 7-(2-Chloro-benzyloxy)-2,2-dimethyl-chroman-5-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from dimethylaluminum chloride (1.0 M in hexanes, 2.9 mL, 2.9 mmol), 5-methyl-2-aminopyridine (314 mg, 2.9 mmol), and a mixture of 5-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-7-carboxylic acid methyl ester and 7-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-5-carboxylic acid methyl ester (374c) (crude 104 mg). Purification by reverse phase chromatography gave 5-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-7-carboxylic acid(5-methyl-pyridin-2-yl)-amide (374) (11 mg, 10% yield) and 7-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-5-carboxylic acid(5-methyl-pyridin-2-yl)-amide (375) as a white solid (25 mg, 23% yield).

Example 374: ¹H NMR (400 MHz, CDCl₃) δ 12.26 (br. s., 1 H) 8.81 (d, J=8.84 Hz, 1 H) 7.99-8.08 (m, 2 H) 7.58 (dd, J=6.95, 2.40 Hz, 1 H) 7.38-7.44 (m, 1 H) 7.33 (s, 1 H) 7.28-7.32 (m, 2 H) 7.23 (s, 1 H) 5.30 (s, 2 H) 2.77 (t, J=6.82 Hz, 2 H) 2.44 (s, 3 H) 1.81 (t, J=6.82 Hz, 2 H) 1.34 (s, 6 H); LCMS for C₂₅H₂₅ClN₂O₃ m/z 436.90 (M+H)⁺; Anal. Calcd. for C₂₅H₂₅ClN₂O₃.1.29TFA: C, 56.72; H, 4.54; N, 4.89; Found: C, 56.68; H, 4.53; N, 4.89.

Example 375: ¹H NMR (400 MHz, CDCl₃) δ 12.27 (s, 1 H) 8.80 (d, J=8.84 Hz, 1 H) 8.00-8.09 (m, 2 H) 7.57 (dd, J=7.45, 1.64 Hz, 1 H) 7.39 (dd, J=7.58, 1.52 Hz, 1 H) 7.23-7.32 (m, 2 H) 6.95 (d, J=2.53 Hz, 1 H) 6.61 (d, J=2.53 Hz, 1 H) 5.20 (s, 2 H) 2.92 (t, J=6.69 Hz, 2 H) 2.45 (s, 3 H) 1.77 (t, J=6.69 Hz, 2 H) 1.36 (s, 6 H); LCMS for C₂₅H₂₅ClN₂O₃ m/z 436.90 (M+H)⁺; Anal. Calcd. for C₂₅H₂₅ClN₂O₃. 1.30TFA: C, 56.65; H, 4.53; N, 4.79; Found: C, 56.51; H, 4.43; N, 4.89.

Preparation of Intermediate 374a 3-Hydroxy-5-(3-methyl-but-2-enyloxy)-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (11.3 g, 67 mmol), potassium carbonate (18.5 g, 134 mmol), and 1-bromo-3-methyl-but-2-ene (10 g, 67 mmol). Purification by column chromatography eluting with 20% EtOAc in hexane gave a pale yellow solid (3.41 g, 20% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.20 (m, 1 H) 7.12-7.17 (m, 1 H) 6.63 (t, J=2.27 Hz, 1 H) 5.41-5.51 (m, 1 H) 5.50 (s, 1H) 4.53 (d, J=6.57 Hz, 2 H) 3.91 (m, 3 H) 1.80 (s, 3 H) 1.69 (s, 3 H); LCMS for C₁₃H₁₆O₄ m/z 237.10 (M+H)⁺.

Preparation of Intermediate 374b 3-(2-Chloro-benzyloxy)-5-(3-methyl-but-2-enyloxy)-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1a, from potassium carbonate (1.25 g, 9.06 mmol), 2-chloro benzyl bromide (0.59 mL, 4.53 mmol), and 3-hydroxy-5-(3-methyl-but-2-enyloxy)-benzoic acid methyl ester (374a) (1.07 g, 4.53 mmol). Purification by flash column chromatography eluting with 5% EtOAc in hexanes gave a colorless oil (1.60 g, 100% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.61 (m, 1 H) 7.37-7.45 (m, 1 H) 7.30 (dd, J=3.92, 2.40 Hz, 2 H) 7.27-7.29 (m, 1 H) 7.24 (dd, J=2.27, 1.26 Hz, 1 H) 6.76 (t, J=2.40 Hz, 1 H) 5.49 (tt, J=6.82, 1.39 Hz, 1 H) 5.15-5.23 (m, 3 H) 4.54 (d, J=6.82 Hz, 2 H) 3.92 (s, 3 H) 1.81 (s, 3 H) 1.73-1.79 (m, 3 H); LCMS for C₂₀H₂₁ClO₄ m/z 383.00 (M+Na)⁺.

Preparation of Intermediate 374c Mixture of 5-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-7-carboxylic acid methyl ester and 7-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-5-carboxylic acid methyl ester

Montarillonite K10 (404 mg) was added to a solution of 3-(2-chloro-benzyloxy)-5-(3-methyl-but-2-enyloxy)-benzoic acid methyl ester (374b) (304 mg, 0.84 mmol) in CCl₄ (3 mL). The suspension was stirred at 50° C. overnight. The mixture was filtered and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexanes to give a mixture of 5-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-7-carboxylic acid methyl ester and 7-(2-chloro-benzyloxy)-2,2-dimethyl-chroman-5-carboxylic acid methyl ester and starting material as colorless oil (104 mg) which was used as is in the next step. LCMS for C₂₀H₂₁Cl₄ m/z 383.00 (M+Na)⁺.

Example 376 2-Methyl-N-(5-methylpyridin-2-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

To a solution of 5-methyl-2-aminopyridine (144 mg, 1.33 mmol) in DCE at 0° C. was added Al(CH₃)₂Cl drop-wise. The reaction was stirred at room temperature for 20 minutes followed by the addition of methyl 2-methyl-7-(4-(methylsulfonyl)phenoxy)-3-oxoisoindoline-5-carboxylate. After stirring the reaction at room temperature for 14 hours, it was diluted with CH₂Cl₂ and quench with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL) slowly. The solution was washed with brine, dried over Na₂SO₄, and concentrated. The crude sample was introduced into a silica gel column and eluted with 5-10% MeOH/CHCl₃ to provide the product (40 mg, 85% yield) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3 H) 3.10 (s, 3 H) 3.19-3.33 (m, 3 H) 4.40 (s, 2 H) 7.19 (d, J=8.67 Hz, 2 H) 7.53-7.66 (m, 1 H) 7.82 (s, 1 H) 7.97 (d, J=8.67 Hz, 2 H) 8.10-8.17 (m, 1 H) 8.19 (s, 2 H) 8.81 (s, 1 H); LC-MS (ESI)+ m/z=452.00 (M+H)⁺.

Preparation of Intermediate 376a Dimethyl 5-(allyloxy)isophthalate

To a mixture of dimethyl 5-hydroxy-isophthalate (10 g, 47.577 mmol), Cs₂CO₃ (31 g, 95.2mmol) in DMF was added allyl bromide (4.83 mL, 57.1 mmol) drop-wise. After stirring the mixture for 14 hours, the reaction was treated with water, extracted with EtOAc (2×). The combined organic extract was dried over sodium sulfate, filtered and evaporated to provide the desired product as white solid (12 g, 100% yield). The crude product was used without further purification. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 6 H) 4.56-4.71 (m, 2 H) 5.33 (dd, J=10.46, 1.41 Hz, 1 H) 5.39-5.53 (m, 1 H) 5.96-6.17 (m, 1 H) 7.76 (d, J=1.32 Hz, 2 H) 8.28 (t, J=1.41 Hz, 1 H); LC-MS: (ESI)+m/z=251.00 (M+1)⁺.

Preparation of Intermediate 376b Dimethyl 4-allyl-5-hydroxyisophthalate

A solution of dimethyl 5-(allyloxy)isophthalate (1.5 g, 5.994 mmol) in N,N-dimethylaniline (15 mL) was heat at 200° C. for 14 hours. After it was cooled to room temperature, the reaction was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried with Na₂SO₄. The solvent was evaporated under reduced pressure. The desired product was purified via silica gel gradient column chromatography with EtOAc/Hex (10-25%) to afford the title compound (750 mg, yield 70%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.82 (d, J=6.22 Hz, 2 H) 3.92 (d, J=5.84 Hz, 6 H) 5.02-5.11 (m, 1 H) 5.10-5.17 (m, 1 H) 5.81 (s, 1 H) 5.90-6.13 (m, 1 H) 7.70 (d, J=1.70 Hz, 1 H) 8.11 (d, J=1.51 Hz, 1 H); LC-MS(ESI)+ m/z=251.00 (M+H)⁺.

Preparation of Intermediate 376c Dimethyl 4-allyl-5-(4-(methylsulfonyl)phenoxy)isophthalate

A mixture of dimethyl 4-allyl-5-hydroxyisophthalate (2.0 g, 7.99 mmol), 4-fluorophenyl methyl sulfone (2.1 g, 12 mmol), Cs₂CO₃ (5.2 g, 16 mmol) and CuI (400 mg, 2.1 mmol) in DMF (20 mL) was heated to for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over Na₂SO₄ and concentrated. The product was purified via silica gel gradient chromatography eluted with EtOAc in hexanes (10/90 to 30/90) to afford the title compound (2.5 g, 78%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.83 (dd, J=6.69, 1.60 Hz, 2 H) 3.03-3.16 (m, 3 H) 3.93 (d, 6 H) 6.14-6.34 (m, 1 H) 6.63 (dd, J=16.11, 1.60 Hz, 1 H) 6.88-6.98 (m, 1 H) 6.97-7.09 (m, 2 H) 7.79 (d, J=1.70 Hz, 1 H) 7.87-8.01 (m, 2 H) 8.29 (d, J=1.70 Hz, 1 H); LC-MS (ESI)+m/z =405.00 (M+H)⁺.

Preparation of Intermediate 376d Dimethyl 5-(4-(methylsulfonyl)phenoxy)-4-(prop-1-enyl)isophthalate

To a solution of dimethyl 4-allyl-5-(4-(methylsulfonyl)phenoxy)isophthalate (3.0 g, 8.814 mmol) in CH₂Cl₂ (25 mL) was added bis(acetonitrile-palladium(II) chloride (229 mg, 0.881 mmol). The mixture was refluxed under N₂ for 14 hours. After removal of the solvent, the crude material was introduced into a silica gel column and eluted with EtOAc in hexanes (10/90 to 30/70) to afford the title compound (2.65 g, 88%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82 (dd, J=6.69, 1.79 Hz, 3 H) 3.04-3.18 (m, 3 H) 3.93 (d, 6 H) 6.00 (none, 1 H) 6.22 (dd, J=16.01, 6.78 Hz, 1 H) 6.62 (dd, J=16.01, 1.70 Hz, 1 H) 6.94-7.09 (m, 2 H) 7.77 (d, J=1.70 Hz, 1 H) 7.85-8.00 (m, 2 H) 8.28 (d, J=1.70 Hz, 1 H); LC-MS(ESI)+ m/z=405.00 (M+H)⁺.

Preparation of Intermediate 376e Dimethyl 4-formyl-5-(4-(methylsulfonyl)-phenoxy)-isophthalate

A solution of dimethyl 5-(4-(methylsulfonyl)phenoxy)-4-(prop-1-enyl)isophthalate (2.6 g, 7.8 mmol) in CH₂Cl₂ and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil, which was introduced into a silica gel column and eluted with 10-30% EtOAc in hexanes to afford the title compound (2.5 g, 98%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.08 (q, 3 H) 3.95 (dd, 6 H) 7.08-7.16 (m, 2 H) 7.98 (q, J=2.07 Hz, 2 H) 7.99-8.03 (m, 1 H) 8.33-8.39 (m, 1 H) 10.46 (s, 1 H); LC-MS (ERS)+ m/z=393.00 (M+H)⁺.

Preparation of Intermediate 376f Methyl 2-methyl-7-(4-(methylsulfonyl)phenoxy)-3-oxoisoindoline-5-carboxylate

A sealed tube was charged with a solution of dimethyl 4-formyl-5-(4-(methylsulfonyl)phenoxy)-isophthalate (210 mg, 0.535 mmol) in MeOH and aminomethane hydrochloride (72.3 mg, 1.07 mmol). After stirring the reaction at room temperature for 2 hours, NaCNBH₃ (84.1 mg, 1.34 mmol) was added. The mixture was then stirred at 65° C. for 14 hours. The solvent was evaporated and replaced with ethyl acetate. The organic layer was then washed with brine (3×), dried over MgSO₄, and concentrated. The crude sample was introduced into a silica gel column chromatography and eluted with 5-10% MeOH/CHCl3 to provide the desired product (100 mg, 50% yield) as white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.09 (s, 3 H) 3.21 (s, 3 H) 3.94 (s, 3 H) 4.36 (s, 2 H) 7.07-7.21 (m, 2 H) 7.84 (d, J=1.13 Hz, 1 H) 7.90-8.03 (m, 2 H) 8.37 (d, J=1.13 Hz, 1 H); LC-MS (ESI)+ m/z=376.00 (M+H)⁺.

Examples 377-388 were prepared in a similar manner as described for Example 376, from the appropriate amino heterocycles and primary amines. For Examples 377 and 378, benzyl bromide was used instead of fluorophenyl sulfone.

Example 377 7-(Benzyloxy)-2-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3-oxoisoindoline-5-carboxamide

Example 378 7-(Benzyloxy)-2-cyclopropyl-N-(5-methylpyridin-2-yl)-3-oxoisoindoline-5-carboxamide

Example 379 2-Ethyl-N-(5-methylpyridin-2-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 380 2-Ethyl-N-(1-methyl-1H-pyrazol-3-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 381 2-Isobutyl-N-(5-methylpyridin-2-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 382 2-Isobutyl-N-(1-methyl-1H-pyrazol-3-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 383 2-Isopropyl-N-(5-methylpyridin-2-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 384 2-Isopropyl-N-(1-methyl-1H-pyrazol-3-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 385 2-Cyclopropyl-N-(5-methylpyridin-2-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 386 2-Cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 387 2-(2-Methoxyethyl)-N-(5-methylpyridin-2-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example 388 2-(2-Methoxyethyl)-N-(1-methyl-1H-pyrazol-3-yl)-7-(4-(methylsulfonyl)-phenoxy)-3-oxoisoindoline-5-carboxamide

Example MW MF NMR m/z 377 402.5 C23H22N4O3 1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.78-1.05 (m, 4 H) 403.00 2.88-3.04 (m, J = 3.96 Hz, 1 H) 3.82 (s, 3 H) 4.33 (s, 2 H) 5.21 (s, 2 H) 6.79 (d, J = 2.26 Hz, 1 H) 7.30 (d, J = 2.26 Hz, 1 H) 7.35-7.50 (m, 5 H) 7.79 (s, 1 H) 7.83 (d, J = 0.94 Hz, 1 H) 8.78 (s, 1 H) 378 413.5 C25H23N3O3 1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.79-1.03 (m, 4 H) 414.00 2.33 (s, 3 H) 2.87-3.09 (m, 1 H) 4.35 (s, 2 H) 5.23 (s, 2 H) 7.34-7.50 (m, 5 H) 7.58 (dd, J = 8.38, 1.98 Hz, 1 H) 7.78 (d, J = 1.13 Hz, 1 H) 7.90 (d, J = 0.94 Hz, 1 H) 8.15 (s, 1 H) 8.24 (d, J = 8.48 Hz, 1 H) 8.71 (s, 1 H) 379 465.5 C24H23N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.29 (t, 3 H) 2.32 (s, 466.00 3 H) 3.10 (s, 3 H) 3.72 (q, 2 H) 4.41 (s, 2 H) 7.20 (dd, 2 H) 7.59 (dd, 1 H) 7.80 (s, 1 H) 7.97 (d, J = 9.04 Hz, 2 H) 8.09-8.29 (m, 3 H) 8.68 (s, 1 H) 380 454.5 C22H22N4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.29 (t, J = 7.25 Hz, 3 455.00 H) 3.10 (s, 3 H) 3.71 (q, 2 H) 3.83 (s, 3 H) 4.41 (s, 2 H) 6.75 (s, 1 H) 7.19 (d, J = 8.67 Hz, 2 H) 7.29 (s, 1 H) 7.79 (s, 1 H) 7.97 (d, J = 8.67 Hz, 2 H) 8.10 (s, 1 H) 8.61 (s, 1 H) 381 493.6 C26H27N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.97 (d, J = 6.59 Hz, 6 494.00 H) 2.00-2.15 (m, 1 H) 2.32 (s, 3 H) 3.10 (s, 3 H) 3.45 (d, J = 7.35 Hz, 2 H) 4.41 (s, 2 H) 7.12-7.25 (m, 2 H) 7.57 (dd, J = 8.38, 2.17 Hz, 1 H) 7.81 (d, J = 1.32 Hz, 1 H) 7.92-8.06 (m, 2 H) 8.14 (s, 1 H) 8.20 (t, J = 4.14 Hz, 2 H) 8.85 (s, 1 H) 382 482.6 C24H26N4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.95 (d, J = 6.59 Hz, 6 483.00 H) 1.77-1.99 (m, 2 H) 1.99-2.16 (m, 1 H) 3.10 (s, 3 H) 3.45 (d, J = 7.54 Hz, 2 H) 3.83 (s, 3 H) 4.40 (s, 2 H) 6.76 (d, J = 1.70 Hz, 1 H) 7.19 (d, J = 8.67 Hz, 2 H) 7.30 (d, J = 1.88 Hz, 1 H) 7.81 (s, 1 H) 7.97 (d, J = 8.67 Hz, 2 H) 8.16 (s, 1 H) 8.98 (s, 1 H) 383 479.6 C25H25N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.32 (d, J = 6.78 Hz, 6 480.00 H) 2.32 (s, 3 H) 3.10 (s, 3 H) 4.39 (s, 2 H) 4.62-4.82 (m, J = 6.59 Hz, 1 H) 7.20 (d, J = 8.85 Hz, 2 H) 7.52-7.65 (m, 1 H) 7.79 (s, 1 H) 7.98 (d, J = 8.67 Hz, 2 H) 8.25 (s, 3 H) 8.72 (s, 1 H) 384 468.5 C23H24N4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.31 (d, J = 6.78 Hz, 6 469.00 H) 3.10 (s, 3 H) 3.83 (s, 3 H) 4.39 (s, 2 H) 4.62-4.80 (m, 1 H) 6.75 (d, J = 2.26 Hz, 1 H) 7.16-7.25 (m, 2 H) 7.30 (d, J = 2.26 Hz, 1 H) 7.78 (d, J = 1.32 Hz, 1 H) 7.93-8.04 (m, 2 H) 8.12 (d, J = 1.13 Hz, 1 H) 8.74 (s, 1 H) 385 477.5 C25H23N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.82-1.04 (m, 4 H) 478.00 2.35 (s, 3 H) 2.87-3.01 (m, 1 H) 3.10 (s, 3 H) 4.35 (s, 2 H) 7.13-7.23 (m, 2 H) 7.68 (d, 1 H) 7.86 (d, J = 1.13 Hz, 1 H) 7.92-8.03 (m, 2 H) 8.09 (s, 1 H) 8.23 (d, J = 1.13 Hz, 1 H) 8.34 (d, 1 H) 9.64 (s, 1 H) 386 466.5 C23H22N4O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.83-1.02 (m, 4 H) 467.00 2.88-3.03 (m, 1 H) 3.10 (s, 3 H) 3.83 (s, 3 H) 4.35 (s, 2 H) 6.76 (d, J = 2.07 Hz, 1 H) 7.11-7.22 (m, 2 H) 7.30 (d, J = 2.26 Hz, 1 H) 7.79 (s, 1 H) 7.97 (d, J = 8.85 Hz, 2 H) 8.11 (s, 1 H) 8.84 (s, 1 H) 387 495.6 C25H25N3O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.33 (s, 3 H) 3.10 (s, 496.00 3 H) 3.36 (s, 3 H) 3.61-3.71 (m, 2 H) 3.82 (t, J = 4.90 Hz, 2 H) 4.56 (s, 2 H) 7.11-7.25 (m, 2 H) 7.59 (dd, J = 8.48, 2.26 Hz, 1 H) 7.81 (d, J = 1.32 Hz, 1 H) 7.92-8.04 (m, 2 H) 8.15 (s, 1 H) 8.17-8.28 (m, 2 H) 8.69 (s, 1 H) 388 484.5 C23H24N4O6S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 3.10 (s, 3 H) 3.35 (s, 485.00 3 H) 3.57-3.71 (m, 2 H) 3.78-3.92 (m, 5 H) 4.55 (s, 2 H) 6.77 (d, J = 2.07 Hz, 1 H) 7.14-7.24 (m, 2 H) 7.30 (d, J = 2.07 Hz, 1 H) 7.80 (d, J = 1.13 Hz, 1 H) 7.92-8.04 (m, 2 H) 8.15 (s, 1 H) 8.79 (s, 1 H)

Example 389 2-Isobutyl-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)-phenoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

To a solution of amino methyl pyrazole (338 mg, 3.48 mmol) in DCE at 0° C. was added drop wise Al(CH₃)₂Cl (4.0 mL, 1.0M). After the addition the ice bath was removed and the reaction was stirred for 20 min at room temperature. Methyl 2-isobutyl-5-[4-(methylsulfonyl)phenoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate was added and the reaction was stirred at room temperature overnight. The sample was diluted with CH₂Cl₂, quenched by the slow addition of with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL) slowly. The sample was washed with brine, dried over Na₂SO₄ and concentrated. The product was purified via silica gel gradient chromatography using MeOH/CHCl₃ (5/95 to 10/90) to provide the desired product (105 mg, 85% yield) as white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.98 (d, J=6.59 Hz, 6 H) 1.97-2.21 (m, 1 H) 2.98 (t, J=6.50 Hz, 2 H) 3.08 (s, 3 H) 3.42 (d, J=7.54 Hz, 2 H) 3.57 (t, J=6.50 Hz, 2 H) 3.83 (s, 3 H) 6.76 (d, J=2.07 Hz, 1 H) 7.08 (d, J=8.85 Hz, 2 H) 7.29 (d, J=2.26 Hz, 1 H) 7.82 (s, 1 H) 7.93 (d, J=8.85 Hz, 2 H) 8.45 (s, 1 H) 8.94 (s, 1 H); MS (ESI, pos): 497.

Preparation of Intermediate 389a Dimethyl 4-allyl-5-(benzyloxy)isophthalate

To a mixture of dimethyl 4-allyl-5-hydroxyisophthalate (376b) (5.05 g, 20.18 mmol) and Cs₂CO₃ (13 g, 40.1 mmol) in CH₃CN (30 mL) was added benzyl bromide (3.6 mL, 30.27 mmol). The mixture was stirred at room temperature for 14 hours. The solution was treated with water, and extracted with EtOAc (2×). The organic layer was dried over sodium sulfate, filtered and evaporated to provide the desired product as white solid (6.5 g, 98% yield). The crude product was used without purification. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.85 (t, J=6.78 Hz, 2 H) 3.89-3.93 (m, 3 H) 3.93 (s, 3 H) 4.93-4.99 (m, 1 H) 4.99-5.07 (m, 1 H) 5.16 (s, 2 H) 5.87-6.11 (m, 1 H) 7.30-7.38 (m, 1 H) 7.39-7.55 (m, 4 H) 7.74 (d, J=1.51 Hz, 1 H) 8.12 (d, J=1.70 Hz, 1 H); MS (ESI, pos):341.

Preparation of Intermediate 389b Dimethyl 5-(benzyloxy)-4-(2-oxoethyl)isophthalate

A solution of dimethyl 4-allyl-5-(benzyloxy)isophthalate (3.5 g, 10.28 mmol) in CH₂Cl₂ and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil which was purified by column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the aldehyde (3.0g, 98%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 3.95 (s, 3 H) 4.29 (s, 2 H) 5.14 (s, 2 H) 7.31-7.56 (m, 5 H) 7.81 (d, J=1.32 Hz, 1 H) 8.29 (d, J=1.51 Hz, 1 H) 9.75 (s, 1 H); MS (ESI, pos): 343.

Preparation of Intermediate 389c Methyl 5-(benzyloxy)-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

To a solution of dimethyl 5-(benzyloxy)-4-(2-oxoethyl)isophthalate (1.5 g, 4.38 mmol) in MeOH was added isobutylamine (385 mg, 0.522 mL, 5.26 mmol). The reaction was stirred at room temperature for 2 hrs, then NaCNBH₃ (84.1 mg, 1.34 mmol) was added. The mixture was stirred at 75° C. overnight. The solvents were removed under reduced pressure, diluted with ethyl acetate and washed with brine (3×). The product was purified via gradient silica gel chromatography using MeOH/CHCl₃ (5/95 to 10/90) to provide the product (1.1 g, 50% yield) as a film ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.96 (dd, 6 H) 1.96-2.16 (m, 1 H) 3.05 (t, J=6.69 Hz, 2 H) 3.36-3.46 (m, J=7.63, 7.63 Hz, 2 H) 3.49-3.62 (m, 2 H) 3.88-4.02 (m, 3 H) 5.16 (s, 2 H) 7.32-7.56 (m, 5 H) 7.74 (d, J=1.32 Hz, 1 H) 8.42 (d, J=1.32 Hz, 1 H); MS (ESI, pos): 368.

Preparation of Intermediate 389d Methyl 5-hydroxy-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

To a solution of methyl 5-(benzyloxy)-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (1 g, 2.72 mmol) in MeOH (10 mL) was added catalyst amount of 10% Pd on C. This mixture was stirred under H₂ balloon at room temperature for 3 hr. The solids were filtered through a bed of Celite. Removal of the solvent gave the product (750 mg, 98%) as light yellow solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (d, 6 H) 1.98-2.16 (m, 1 H) 3.05 (t, J=6.59 Hz, 2 H) 3.38-3.50 (m, 2 H) 3.57 (t, J=6.69 Hz, 2 H) 3.82-3.93 (m, 3 H) 7.50 (s, 1 H) 7.74 (d, J=1.51 Hz, 1 H) 8.30 (d, J=1.32 Hz, 1 H); MS (ESI, pos): 278.

Preparation of Intermediate 389e Methyl 2-isobutyl-5-[4-(methylsulfonyl)phenoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

A mixture of methyl 5-hydroxy-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (250 mg, 0.90 mmol), 4-fluorophenyl methyl sulfone (236 mg, 1.35 mmol), Cs₂CO₃ (441 mg, 1.35 mmol) and Cul (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na₂SO₄ and concentrated. The product was purified via column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the ether (312 mg, 78%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.78 Hz, 6 H) 1.94-2.16 (m, 1 H) 2.94 (t, J=6.59 Hz, 2 H) 3.04-3.16 (m, 3 H) 3.41 (d, J=7.54 Hz, 2 H) 3.55 (t, J=6.59 Hz, 2 H) 3.87-4.01 (m, 3 H) 7.00-7.11 (m, 2 H) 7.80 (d, J=1.70 Hz, 1 H) 7.88-8.00 (m, 2 H) 8.66 (d, J=1.51 Hz, 1 H); MS (ESI, pos): 432.

Examples 390-393 were prepared in a similar manner as described for Example 376, from the appropriate amino heterocycles, primary amines, and fluorophenyl intermediates. Example 394 was isolated as a minor side product during the preparation of Example 390, from methyl 5-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (hydrogenation of methyl 5-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate gave methyl 5-hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-7-carboxylate as the side product).

Example 390 2-Methyl-N-(5-methylpyridin-2-yl)-5-(4-(methylsulfonyl)-phenoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

Example 391 2-Isobutyl-N-(5-methylpyridin-2-yl)-5-(4-(methylsulfonyl)-phenoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

Example 392 5-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-2-isobutyl-N-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

Example 393 5-(4-(Dimethylcarbamoyl)-3-fluorophenoxy)-2-isobutyl-N-(5-methylpyridin-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

Example 394 2-Methyl-N-(5-methylpyridin-2-yl)-5-(4-(methylsulfonyl)-phenoxy)-1-oxo-1,2-dihydroisoquinoline-7-carboxamide

Example MW MF NMR m/z 390 465.5 C24H23N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 466.10 2.36 (s, 3 H) 3.01 (t, J = 6.69 Hz, 2 H) 3.08 (s, 3 H) 3.20 (s, 3 H) 3.60 (t, J = 6.69 Hz, 2 H) 7.09 (d, J = 8.85 Hz, 2 H) 7.69 (dd, J = 8.67, 1.70 Hz, 1 H) 7.85-7.98 (m, 3 H) 8.11 (d, J = 0.94 Hz, 1 H) 8.37 (d, J = 8.67 Hz, 1 H) 8.57 (d, J = 1.51 Hz, 1 H) 9.67 (s, 1 H) 391 507.6 C27H29N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 508.00 0.99 (d, J = 6.59 Hz, 6 H) 1.98-2.15 (m, 1 H) 2.32 (s, 3 H) 2.98 (t, J = 6.59 Hz, 2 H) 3.08 (s, 3 H) 3.43 (d, J = 7.54 Hz, 2 H) 3.58 (t, J = 6.50 Hz, 2 H) 7.08 (d, J = 8.85 Hz, 2 H) 7.58 (d, 1 H) 7.82 (s, 1 H) 7.93 (d, J = 8.85 Hz, 2 H) 8.11-8.30 (m, 2 H) 8.49 (s, 1 H) 8.71 (s, 1 H) 392 507.6 C27H30FN5O4 1H NMR (300 MHz, CHLOROFORM-d) d ppm 508.00 0.98 (d, J = 6.59 Hz, 6 H) 1.98-2.17 (m, 1 H) 2.86-3.06 (m, 5 H) 3.12 (s, 3 H) 3.42 (d, J = 7.35 Hz, 2 H) 3.56 (t, 2 H) 3.83 (s, 3 H) 6.58-6.70 (m, 1 H) 6.71-6.86 (m, 2 H) 7.28-7.32 (m, 1 H) 7.33-7.45 (m, 1 H) 7.82 (s, 1 H) 8.40 (s, 1 H) 8.68 (s, 1 H) 393 518.6 C29H31FN4O4 1H NMR (300 MHz, CHLOROFORM-d) d ppm 519.00 0.92 (d, J = 6.59 Hz, 6 H) 1.90-2.09 (m, 1 H) 2.48 (s, 3 H) 2.97 (s, 3 H) 2.99-3.08 (m, 2 H) 3.16 (s, 3 H) 3.33-3.44 (m, 2 H) 3.52-3.65 (m, 2 H) 6.54-6.78 (m, 2 H) 7.18 (d, 1 H) 7.58 (s, 1 H) 7.97 (d, 1 H) 8.14 (d, 1 H) 8.26 (s, 1 H) 8.50 (s, 1 H) 12.05 (s, 1 H) 394 463.5 C24H21N3O5S 1H NMR (300 MHz, CHLOROFORM-d) d ppm 464.10 2.33 (s, 3 H) 3.08 (s, 3 H) 3.66 (s, 3 H) 6.67 (d, J = 7.54 Hz, 1 H) 7.07-7.17 (m, 2 H) 7.21 (d, J = 7.54 Hz, 1 H) 7.51-7.66 (m, 1 H) 7.86-7.99 (m, 3 H) 8.15 (s, 1 H) 8.23 (d, 1 H) 8.82 (s, 1 H) 8.90 (br. s., 1 H)

Example 395 7-Methoxy-2,2-dimethyl-N-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-5-carboxamide

To a solution of 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (24 g, 0.11 mol) in CH₂Cl₂(500 mL) were added EDCI (31.6 g, 1.08 mol), NMM (54.5 g, 0.54 mol), HOBt (22 g, 0.16 mol) and 1-methyl-1H-pyrazol-3-ylamine (11 g, 0.11 mol) sequentially. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/1) showed the reaction was complete. The mixture was washed with water (250 mL), sat. aq. citric acid (250 mL×2), sat. NaHCO₃ (250 mL) and brine (250 mL) sequentially. The organic phase was dried over Na₂SO₄ and concentrated to give a white solid. The crude solid was purified by column chromatography (EtOAc/petroleum ether=1/10˜1/1) to give the title compound (9.6 g, 30%) as a white solid. ¹H NMR (400 MHz, DMSO): δ 10.49 (s, 1H), 7.49 (s, 1H), 7.44 (s, 2H), 6.48 (s, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.96 (s, 2H), 1.35 (s, 6H).

Preparation of Intermediate 395a Methyl 3-methoxy-4-(2-methylallyloxy)benzoate

To a suspension of methyl 4-hydroxy-3-methoxybenzoate (100 g, 0.55 mol) and K₂CO₃ (92 g, 0.66 mol) in DMF (800 ml) was added drop wise 3-chloro-2-methyl-propene (55 g, 0.60 mol). The mixture was stirred at 60° C. overnight. TLC (EtOAc/petroleum ether=1/3) showed no starting material was present. The reaction mixture was filtered and the filtrate was added water (400 ml). The mixture was extracted with EtOAc (400 ml×3). The combined organic phase was washed with brine (400 mL), dried (Na₂SO₄) and concentrated to give the product (130 g, 100%) as yellow oil. The oil was used directly to the next step without further purification. ¹H NMR (400 MHz, CDCl₃): δ 7.54 (d, 1H), 7.19 (s, 1H), 6.80 (d, 1H), 5.00(d, 2H), 4.50 (s, 2H), 3.83 (d, 6H), 1.76 (s, 3H).

Preparation of Intermediate 395b Methyl 4-hydroxy-3-methoxy-5-(2-methylallyl)benzoate

A solution of methyl 3-methoxy-4-(2-methylallyloxy)benzoate (130 g, 0.55 mol) in NMP (500 mL) was heated to reflux for 6 h. TLC (EtOAc/petroleum ether=1/5) showed the reaction was complete. The mixture was washed with 1 N aq. HCl and extracted with EtOAc (250 mL×3). The combined organic phases were washed with brine (400 mL), dried over Na₂SO₄ and concentrated to give the product (150 g, 100%) as a brown oil. The oil was used directly to the next step without further purification.

Preparation of Intermediate 395c Methyl 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylate

A solution of methyl 4-hydroxy-3-methoxy-5-(2-methylallyl)benzoate (150 g, 0.63 mol) in conc. HCl (300 mL) and MeOH (300 mL) was heated to reflux for 2 h. TLC (EtOAc/petroleum ether=1/5) showed the reaction was complete. The solution was evaporated, and the residue was extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over Na₂SO₄ and concentrated to give a brown oil. The crude oil was purified by column chromatography (EtOAc/petroleum ether=1/30) to give the title compound (80 g, 53%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.51 (s, 1H), 7.46 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.05 (s, 2H), 1.53 (s, 6H).

Preparation of Intermediate 395d 7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid

To a solution of methyl 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylate (40 g, 0.17 mol) in MeOH (200 mL) was added NaOH (34 g, 0.85 mol) in one portion. The mixture was stirred at room temperature for 24 h. TLC (EtOAc/petroleum ether=1/1) showed the reaction was complete. Then MeOH was removed under vacuum. The residue was dissolved in water (100 mL), and the solution was acidified with conc. HCl. The solid was filtered and the filter cake was dried in vacuo to give the title compound (25 g, 68%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.62 (s, 1H), 7.54 (s, 1H), 3.94 (s, 3H), 3.00 (s, 2H), 1.50 (s, 6H).

Example 396 4-[5-(Azetidine-1-carbonyl)-pyrazin-2-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 1, from 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyrazine-2-carboxylic acid methyl ester (396a) and azetidine. ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J=1.26 Hz, 1 H) 8.35 (d, J=1.26 Hz, 1 H) 8.30 (s, 1 H) 7.23-7.32 (m, 1 H) 7.18 (d, J=1.26 Hz, 1 H) 7.12 (d, J=1.26 Hz, 1 H) 6.79 (d, J=2.27 Hz, 1 H) 4.70 (t, J=7.83 Hz, 2 H) 4.27 (t, J=7.83 Hz, 2 H) 3.81 (s, 3 H) 2.85 (s, 2 H) 2.31-2.46 (m, 2 H) 1.49 (s, 6 H); LCMS for C₂₃H₂₄N₆O₄ m/z 449.20 (M+H^(±)); Anal. Calcd. for C₂₃H₂₄N₆O₄.0.18 AcOH: C, 61.09; H, 5.43; N, 18.30; Found: C, 61.21; H, 5.64; N, 18.31.

Preparation of Intermediate 396a 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyrazine-2-carboxylic acid methyl ester

A mixture of methyl 5-chloropyrazine-2-carboxylate (60.1 mg, 0.348 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (100 mg, 0.348 mmol) and Cs₂CO₃ (227 mg, 0.696 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H₂O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography eluting with 45% to 70% EtOAc in hexanes to give a colorless thick oil (71 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1 H) 8.85 (d, J=1.01 Hz, 1 H) 8.52 (d, J=1.26 Hz, 1 H) 7.27 (d, J=2.27 Hz, 1 H) 7.21 (s, 1 H) 7.15 (s, 1 H) 6.80 (d, J=2.02 Hz, 1 H) 4.03 (s, 3 H) 3.74 (s, 3 H) 2.86 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₁H₂₁N₅O₅ m/z 424.20 (M+H⁺).

Examples 397-399 were prepared in a similar manner as described for Example 176, from 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid (180) and the appropriate amines.

Example 397 4-[6-(3-Fluoro-azetidine-1-carbonyl)-pyridin-3-yloxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

¹H NMR (400 MHz, CDCl₃) δ 9.75 (s, 1 H) 8.33 (d, J=2.78 Hz, 1 H) 8.13 (d, J=8.84 Hz, 1 H) 7.37 (dd, J=8.72, 2.91 Hz, 1 H) 7.24-7.30 (m, 1 H) 7.21 (s, 1 H) 7.16 (d, J=1.26 Hz, 1 H) 6.85 (d, J=2.27 Hz, 1 H) 5.22-5.50 (m, 1 H) 4.90-5.07 (m, 1 H) 4.71-4.88 (m, 1 H) 4.41-4.61 (m, 1 H) 4.24-4.39 (m, 1 H) 3.79 (s, 3 H) 2.91 (s, 2 H) 1.50 (s, 6 H); LCMS for C₂₄H₂₄FN₅O₄ m/z 466.20 (M+H⁺); Anal. Calcd. for C₂₄H₂₄FN₅O₄.0.30 AcOH.0.35H₂O: C, 60.32; H, 5.33; N, 14.30; Found: C, 60.25; H, 5.32; N, 14.37.

Example 398 2,2-Dimethyl-4-[6-(pyrrolidine-1-carbonyl)-pyridin-3-yloxy]-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1 H) 8.33 (br, s, 1 H) 7.90 (br, s, 1 H) 7.34 (dd, J=8.59, 2.53 Hz, 1 H) 7.24-7.28 (m, 1 H) 7.07 (d, J=8.34 Hz, 2 H) 6.79 (d, J=2.02 Hz, 1 H) 3.76-3.89 (m, 5 H) 3.69 (t, J=6.69 Hz, 2 H), 2.92 (s, 2 H) 1.94 (t, J=6.69 Hz, 4 H), 1.50 (s, 6 H); LCMS for C₂₅H₂₇N₅O₄ m/z 462.20 (M+H⁺); Anal. Calcd. for C₂₅H₂₇N₅O₄.0.30 AcOH.0.20 H₂O: C, 63.64; H, 5.97; N, 14.50; Found: C, 63.63; H, 5.99; N, 14.53.

Example 399 5-[2,2-Dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyridine-2-carboxylic acid cyanomethyl-methyl-amide

¹H NMR (400 MHz, CDCl₃) δ 8.71 (br. s., 1 H) 8.34 (d, J=2.78 Hz, 1 H) 7.73-8.07 (m, 1 H) 7.37 (d, J=3.03 Hz, 1 H) 7.25-7.30 (m, 1 H) 7.09 (d, J=5.81 Hz, 2 H) 6.79 (d, J=2.27 Hz, 1 H) 4.88 (s, 1 H) 4.50 (s, 1 H) 3.79 (s, 3 H) 3.39 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C₂₄H₂₄N₆O₄ m/z 461.20 (M+H⁺); Anal. Calcd. for C₂₄H₂₄N₆O₄.0.25 AcOH.0.75H₂O: C, 60.18; H, 5.46; N, 17.19; Found: C, 59.82; H, 5.25; N, 17.31.

Example 400 4-(3,5-Difluoro-4-methylcarbamoyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide

The title compound was prepared in a similar manner as described for Example 112. ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1 H) 7.10 (d, J=1.01 Hz, 1 H) 6.95 (d, J=1.26 Hz, 1 H) 6.73 (d, J=2.27 Hz, 2 H) 6.47 (d, J=8.59 Hz, 2 H) 3.71 (s, 3 H) 3.02 (d, J=5.05 Hz, 3 H) 2.93 (s, 2 H) 1.51 (s, 6 H); LCMS for C₂₃H₂₂F₂N₄O₄ m/z 457.20 (M+H)⁺; Anal. Calcd. for for C₂₃H₂₂F₂N₄O₄.0.36H₂O: C, 59.67; H, 4.95; N, 12.10; Found: C, 59.68; H, 4.94; N, 12.09.

Example 401 (+)-4-(4-Cyclopropanesulfonyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide and Example 402: (−)-4-(4-Cyclopropanesulfonyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid(5-methyl-pyridin-2-yl)-amide

The title compound was prepared in a similar manner as described for Example 245, followed by chiral separation by SFC column chromatography.

Example 401: [α]_(D)=+15.15, 100% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 1 H) 8.23 (d, J=8.34 Hz, 1 H) 8.12 (s, 1 H) 7.99 (dd, J=8.84, 6.06 Hz, 1 H) 7.58 (dd, J=8.46, 1.89 Hz, 1 H) 7.16-7.24 (m, 2 H) 6.94 (ddd, J=8.84, 7.58, 2.27 Hz, 1 H) 6.62 (dd, J=9.60, 2.27 Hz, 1 H) 3.74 (dd, J=12.13, 5.31 Hz, 1 H) 3.62 (d, J=6.82 Hz, 1 H) 3.15-3.25 (m, 1 H) 2.92-3.00 (m, 1 H) 2.85 (d, J=16.67 Hz, 1 H) 2.32 (s, 3 H) 1.46 (s, 3 H) 1.33-1.43 (m, 2 H) 1.04-1.14 (m, 2 H); LCMS for C₂₆H₂₅FN₂O₆S m/z 513.20 (M+H)⁺; Anal. Calcd. for C₂₆H₂₅FN₂O₆S.0.12H₂O: C, 60.67; H, 4.94; N, 5.44; Found: C, 60.66; H, 4.93; N, 5.19.

Example 402: [α]_(D)=−21.76, 97.2% ee; ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1 H) 8.23 (d, J=8.34 Hz, 1 H) 8.12 (s, 1 H) 7.99 (dd, J=8.72, 6.44 Hz, 1 H) 7.58 (dd, J=8.21, 2.15 Hz, 1 H) 7.18-7.24 (m, 2 H) 6.90-7.00 (m, 1 H) 6.62 (dd, J=9.60, 2.27 Hz, 1 H) 3.75 (d, J=12.13 Hz, 1 H) 3.57-3.68 (m, 1 H) 3.20 (d, J=16.67 Hz, 1 H) 2.90-3.01 (m, 1 H) 2.85 (d, J=16.67 Hz, 1 H) 2.32 (s, 3 H) 1.46 (s, 3 H) 1.32-1.42 (m, 3 H) 1.09 (d, J=7.83 Hz, 2 H); LCMS for C₂₆H₂₅FN₂O₆S m/z 513.20 (M+H)⁺; Anal. Calcd. for C₂₆H₂₅FN₂O₆S.0.10H₂O: C, 60.71; H, 4.94; N, 5.45; Found: C, 60.82; H, 4.91; N, 5.20.

Preparation of sulfonamide intermediate: 4-fluoro-N,N-dimethylbenzenesulfonamide

To a solution of dimethylamine (27.7 g, 342.2 mmol) in THF (172 mL) was added CH₂Cl₂ (300 mL) at 0° C., then DIPEA (127.8 mL, 773.2 mmol) was added, followed by a solution of 4-fluorobenzene-1-sulfonyl chloride (60 g, 309.2 mmol) in CH₂Cl₂ (200 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. TLC (Petroleum ether:EtOAc=5:1) indicated the reaction was complete. Water (200 mL) and 1 N HCl (380 mL) were added. The organic layer was separated and evaporated under reduced pressure to afford the crude product. The crude product was washed with petroleum ether to give the title compound (52.5 g) as a white solid. Yield: 83.7%.

Preparation of sulfonamide intermediate: 1-(4-fluorophenylsulfonyl)azetidine

To a solution of KHMDS (62.0 g, 311.5 mmol) in THF (400 mL) was added drop wise azetidine (16.9 g, 296.5 mmol) at 0° C. under nitrogen atmosphere, and the reaction mixture was stirred for 10 minutes. A solution of 4-fluorobenzene-1-sulfonyl chloride (57.5 g, 296.5 mmol) in THF (200 mL) was added drop wise subsequently and the reaction mixture was allowed to warm to ambient temperature overnight. TLC (Petroleum ether:EtOAc=5:1) indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 mL×3) and water (100 mL). The organic layer was separated and dried over Na₂SO₄, filtered and concentrated to give the title compound (38.5 g) as a pale yellow solid. Yield: 60.4%.

In analogous fashion, the following sulfonamide intermediates were prepared.

¹H NMR (400 MHz, CDCl₃) δ 7.86-7.93 (m, J=8.34, 8.34, 6.32 Hz, 1 H) 6.95-7.05 (m, 2 H) 2.84 (s, 3 H) 2.84 (s, 3 H); LCMS for C₈H₉F₂NO₂S m/z 222.00 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.74 (td, J=8.84, 6.06 Hz, 1 H) 7.11 (td, J=9.22, 6.06 Hz, 1 H) 2.87 (s, 3 H) 2.86 (s, 3 H).

Preparation of sulfone intermediate: 1,2-difluoro-4-(methylsulfonyl)benzene

Iodomethane (15 mL, 0.22 mol) was added to a stirred mixture of 3,4-difluorobenzenethiol (30 g, 0.21 mol) and potassium carbonate (32.6 g, 0.24 mol) in DMF (250 mL), and left overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl ether (100 mL×3), the organic phases were dried over Na₂SO₄ and evaporated under reduced pressure to give (3,4-difluorophenyl)(methyl)sulfane as a yellow liquid. Yield: 30 g, 89.3%. 3-Chloroperoxybenzoic acid (85% in purity, 62.5 g, 0.305 mol) was added in portions to a solution of (3,4-difluorophenyl)(methyl)sulfane (25 g, 0.155 mol) in dichloromethane (650 mL), and the mixture was stirred at room temperature for 2 h. The mixture was washed with saturated aqueous sodium sulfite solution (200 mL). The organic phases were sequentially washed with aqueous sodium bicarbonate solution (100 mL×2) and water (100 mL), dried over Na₂SO₄ and evaporated under reduced pressure to give the title compound as a white solid. Yield: 18 g, 60%.

Preparation of sulfone intermediate: 2-chloro-1-fluoro-4-(methylsulfonyl)benzene

To a stirred mixture of 3-chloro-4-fluorobenzenethiol (65 g, 0.403 mol) and potassium carbonate (54 g, 0.39 mol) in DMF (450 mL) was added drop wise CH₃I (24.96 mL, 0.442 mol) at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl ether (150 mL×3), the combined organic phases were dried over Na₂SO₄ and evaporated under reduced pressure to give (3-chloro-4-fluorophenyl)(methyl)sulfane (70 g, 98%) as a yellow liquid. To a solution of (3-chloro-4-fluorophenyl)(methyl)sulfane (66 g, 0.37 mol) in dichloromethane (1600 mL) was added 3-chloroperoxybenzoic acid (85% purity, 157 g, 0.77 mol) in portions, and the mixture was stirred at room temperature for 2 h. Then the mixture was washed with saturated aqueous sodium sulfite (600 mL). The organic phases were separated and sequentially washed with saturated aqueous sodium bicarbonate (250 mL×2) and water (250 mL), dried over Na₂SO₄ and evaporated under reduced pressure to give a yellow solid. The crude product was re-crystallized from ether (200 mL) to give the title compound (39.45 g, 51%) as a white solid.

Preparation of sulfone intermediate: 2-chloro-4-fluoro-1-(methylsulfonyl)benzene

To a stirred mixture of 2-chloro-4-fluorobenzenethiol (65 g, 0.403 mol) and potassium carbonate (54 g, 0.39 mol) in DMF (450 mL) was added drop wise CH₃I (24.96 mL, 0.442 mol) at room temperature and the mixture was stirred overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl ether (150 mL×3), the combined organic phases were dried over Na₂SO₄ and evaporated under reduced pressure to give (2-chloro-4-fluorophenyl)(methyl)sulfane (70 g, 98%) as a yellow liquid. To a solution of (2-chloro-4-fluorophenyl)(methyl)sulfane (66 g, 0.37 mol) in dichloromethane (1600 mL) was added 3-chloroperoxybenzoic acid (85% purity, 157 g, 0.77 mol) in portions, and the mixture was stirred at room temperature for 2 h. The mixture was washed with aq. saturated sodium sulfite solution (600 mL). The organic phase was separated and sequentially washed with aq. sodium bicarbonate solution (250 mL×2) and water (250 mL), dried over Na₂SO₄ and evaporated under reduced pressure to give a yellow solid. The crude product was re-crystallized from ether (200 mL) to give the title compound (33.1 g, 43%) as a white solid.

Preparation of sulfone intermediate: 1-(ethylsulfonyl)-4-fluorobenzene

To a stirred solution of 4-fluorobenzenethiol (80 g, 0.625 mol) and bromoethane (71.88 g, 0.666 mol) in DMF (1.25 L) under nitrogen atmosphere, Cs₂CO₃ (213.75 g, 0.666 mol) was added. The reaction mixture was stirred at 25° C. overnight. TLC (petroleum ether) indicated the reaction was complete. The mixture was diluted with water (800 mL), extracted with ethyl acetate (600 mL×3). The combined organic layers were washed with water (500 mL×2) and brine (500 mL), dried over Na₂SO₄ and concentrated in vacuum to give ethyl(4-fluorophenyl)sulfane (60 g, 61.5%) as a colorless oil. A mixture of ethyl(4-fluorophenyl)sulfane (60 g, 0.38 mol), acetic acid (1 L) and 30% H₂O₂ (180 mL) was stirred at reflux under N₂ overnight. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. After cooled to room temperature, the reaction mixture was poured into water (500 mL). Then NaHSO₃ (200 g) was add. The mixture was extracted with ethyl acetate (500 mL×3), dried over Na₂SO₄ and concentrated in vacuum to remove the remaining acetic acid. Then the residue was poured into saturated aq. NaOH (800 mL) and extracted with ethyl acetate (500 mL×3) again. The organic layer was dried over Na₂SO₄ and concentrated in vacuum to give the title compound (66 g, 92.4%) as a colorless liquid.

Preparation of sulfone intermediate: 1-(cyclopropylsulfonyl)-4-fluorobenzene

To a stirred solution of 4-fluorobenzenethiol (134 g, 1.05 mol) in DMSO (3 L) under nitrogen atmosphere were added cyclopropyl bromide (140 g, 1.15 mol) and t-BuONa (138.7 g, 1.44 mol). Then the reaction mixture was heated to 80° C. and stirred for 2 days. TLC (petroleum ether) indicated the reaction was complete. After cooled to room temperature, the mixture was poured into water (2 L), extracted with diethyl ether (1.5 L×3). The combined organic phases were washed with water (1 L), then brine (1 L), dried over Na₂SO₄ and concentrated in vacuum to give cyclopropyl(4-fluorophenyl)sulfane (129 g, 73.1%) as a colorless oil. To a mixture of cyclopropyl(4-fluorophenyl)sulfane (129 g, 0.77 mol) and acetic acid (1.9 L) was added 30% H₂O₂ (1.2 L), and the mixture was heated to reflux and stirred overnight. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. After cooled to room temperature, the mixture was poured into water (1 L), then Na₂S₂O₃ (200 g) was added to consume excess H₂O₂, then Na₂CO₃ was added to adjust pH =7. The mixture was extracted with ethyl acetate (1.5 L×2). The combined organic layers were washed with water (1 L), dried over Na₂SO₄ and concentrated in vacuum to give 69 g of crude product, which was purified by column chromatography (25% ethyl acetate in petroleum ether) to give the title compound (42 g, 27.3%) as a white solid.

Preparation of sulfone intermediate: 1-(cyclobutylsulfonyl)-4-fluorobenzene

A suspension of 4-fluorobenzenethiol (80 g, 0.625 mol), cyclobutylbromide (45 g, 0.33 mol) and Cs₂CO₃ (108 g, 0.33 mol) in DMSO (1.5 L) was heated to 70° C. and stirred overnight. TLC (petroleum ether) indicated the reaction was complete. After cooled to room temperature, the reaction mixture was filtered to remove inorganic salts, and the filtrate was partitioned between diethyl ether (1.5 L) and water (1 L). The aqueous layer was extracted with diethyl ether (700 mL×3). The combined organic phases were washed sequentially with water (1 L×2), then brine (1 L), dried over MgSO₄ and concentrated in vacuum to give cyclobutyl(4-fluorophenyl)sulfane (64.8 g, 84.8%) as a pale yellow oil. Cyclobutyl(4-fluorophenyl)sulfane (61.8 g, 0.34 mol) was dissolved in CH₂Cl₂ (2 L) and cooled to −15° C., m-CPBA (150.4 g, 0.742 mol) was added portion wise while keeping the temperature between −15° C. and −10° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 3-4 h. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. The reaction mixture was partitioned between CH₂Cl₂ (2 L) and water (1 L). The organic layer was washed with saturated NaHCO₃ solution (1 L) and brine (1 L), dried over MgSO₄, filtrated and concentrated in vacuum to give the title compound (59 g, 81.1%) as a white solid.

In analogous fashion, the following sulfone intermediates were prepared.

¹H NMR (400 MHz, CDCl₃) δ 7.98 (td, J=8.34, 6.06 Hz, 1 H) 7.05-7.11 (m, 1 H) 7.01 (ddd, J=10.04, 8.15, 2.27 Hz, 1 H) 3.32 (q, J=7.75 Hz, 2 H) 1.32 (t, J=7.33 Hz, 3 H).

¹H NMR (400 MHz, CDCl₃) δ 7.93 (td, J=8.27, 6.44 Hz, 1 H) 6.98-7.09 (m, 2 H) 2.69-2.78 (m, 1 H) 1.34-1.44 (m, 2 H) 1.06-1.16 (m, 2 H).

Methods for Chiral Separation by SFC:

Preparative enantio separation methods were developed using supercritical fluid chromatography (SFC) technology, with supercritical carbon dioxide providing the bulk of the mobile phase. The separation and isolation of enantiomers was carried out on a Berger SFC MultiGram™ Purification System (Mettler Toledo AutoChem, Inc). Since the preparative chromatography conditions used to separate the enantiomers may vary in the type of chiral stationary phase used, the composition of the mobile phase modifier, or even the pressure and flow rates, all methods are described below following the compounds that were separated by those conditions:

Example A: Chiralcel OJ-H (Cellulose tris-(4-methylbenzoate coated on silica)), 250×21 mm, 5μ semi-preparative column was used as the chiral stationary phase (Chiral Technologies, Inc.). Column temperature was maintained at 35° C. The mobile phase used was supercritical CO₂ with methanol as the modifier (range from 20% to 40% depending on the enantiomers to be separated), maintained isocratically at a flow rate of 50-55 mL/min and a constant pressure of 120-140 bar. UV detection at 260 nm was achieved.

Example B: Chiralpak AS-H (amylose tris-(3,5-dimethylphenylcarbamate) 250×21 mm, 5μ semi-preparative column was used as the chiral stationary phase (Chiral Technologies, Inc.). Column temperature was maintained at 35° C. The mobile phase used was supercritical CO₂ with 40% methanol as the modifier, maintained isocratically at a flow rate of 55 mL/min and a constant pressure of 140 bar. UV detection at 260 nm was achieved.

Example C: Chiralcel OD-H (Cellulose tris-(3,5-dimethylphenylcarbamate coated on silica)), 250×21 mm, 5μ semi-preparative column was used as the chiral stationary phase (Chiral Technologies, Inc.). Column temperature was maintained at 35° C. The mobile phase used was supercritical CO₂ with 25% methanol with 0.1% diethylamine as the modifier, maintained isocratically at a flow rate of 55 mL/min and a constant pressure of 140 bar. UV detection at 260 nm was achieved.

Example 403 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-N-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-6-carboxamide

To a solution of 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid (1.360 g, 3.363 mmol), 3-amino-1-methyl-pyrazole (653 mg, 6.730 mmol), and triethylamine (0.94 ml, 6.730 mmol) in 20 mL of DCE was added HATU (2.56 g, 6.730 mmol). The mixture was stirred at 60° C. for 2 hr, quenched with water, and extracted with 3×CHCl₃. The combined organic layer was washed with 2×H₂O, dried with Na₂SO₄, and concentrated to provide an oil that was purified by SFC to give a white solid (874 mg, 54% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.30 (s, 1 H) 8.20 (d, J=2.02 Hz, 1 H) 7.24-7.33 (m, 2 H) 7.15-7.22 (m, 1 H) 7.09 (dd, J=10.86, 2.27 Hz, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.37 (d, J=56.84 Hz, 1 H) 4.62-4.79 (m, 1 H) 4.53 (dd, J=12.13, 1.77 Hz, 2 H) 4.27-4.42 (m, 1 H) 3.80 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C₂₄H₂₃F₂N5O4 m/z 484.20 (M+H)⁺.

Preparation for Intermediate 3a 3-Hydroxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (15.0 g, 89.2 mmol), potassium carbonate (24.7 g, 178.4 mmol) and 3-bromo-2-methyl-propene (9.0 mL, 89.2 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.80 g, 39% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.22 (m, 2 H) 6.66 (t, J=2.27 Hz, 1 H) 5.81 (s, 1 H) 5.06-5.16 (m, 1 H) 4.93-5.04 (m, 1 H) 4.44 (s, 2 H) 3.91 (s, 3 H) 1.68-1.94 (m, 3 H); LCMS for C₁₂H₁₄O₄ m/z 223.10 (M+H)⁺.

Preparation of Intermediate 3b 3-Methoxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1b, from 3-methoxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester (3a) (7.80 g, 35.0 mmol), methyl iodide (2.60 mL, 42.0 mmol) and K₂CO₃ (9.67 g, 70.0 mmol). Purification by column chromatography eluting with 10% EtOAc in hexanes gave a colorless oil (7.54 g, 91% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.22 (m, 1 H) 7.18-7.20 (m, 1 H) 6.68 (t, J=2.27 Hz, 1 H) 5.11 (s, 1 H) 5.01 (s, 1 H) 4.46 (s, 2 H) 3.91 (s, 3 H) 3.83 (s, 3 H) 1.84 (s, 3 H); LCMS for C₁₃H₁₆O₄ m/z 237.10 (M+H)⁺.

Preparation of Intermediate 3c Mixture of 3-hydroxy-5-methoxy-2-(2-methyl-allyl)-benzoic acid methyl ester and 3-hydroxy-5-methoxy-4-(2-methyl-allyl)-benzoic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1c, from 3-methoxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester (3b) (7.54 g, 32.0 mmol). Purification by column chromatography eluting with 5-20% EtOAc in hexanes gave a mixture of 3-hydroxy-5-methoxy-2-(2-methyl-allyl)-benzoic acid methyl ester and 3-hydroxy-5-methoxy-4-(2-methyl-allyl)-benzoic acid methyl ester as a colorless oil (4.80 g, 64% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.24 (m) 7.02 (d, J=2.27 Hz) 6.68 (t, J=2.40 Hz) 6.51 (d, J=2.27 Hz) 5.10 (s) 5.00 (s) 3.91 (s) 3.88 (s) 3.83 (s) 3.80 (s) 3.26 (s) 1.83 (s) 1.47 (s); LCMS for C₁₃H₁₆O₄ m/z 237.10 (M+H)⁺.

Preparation of Intermediate 3d Mixture of 4-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester and 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner as described for Intermediate 1d, from zirconium(IV) chloride (3.03 g, 11.0 mmol) and a mixture of methyl 2-ally-3-hydroxy-5-methoxy-benzoate and methyl 2-ally-3-hydroxy-5-methoxybenzoate (3c) (2.5 g, 13.0 mmol). Purification by column chromatography eluting with 5-10% EtOAc in hexanes gave a mixture of 4-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-4-carboxylic acid methyl ester (2:1) as a colorless oil (1.74 g, 70% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.12 (s) 7.07 (s) 7.03 (d, J=2.27 Hz) 6.52 (d, J=2.27 Hz) 3.90 (s) 3.87 (s) 3.81 (s) 3.27 (s) 2.97 (s) 1.49 (s) 1.48 (s); LCMS for C₁₃H₁₆O₄ m/z 237.10 (M+H)⁺.

Preparation of Intermediate 3e 4-Hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxy-lic acid methyl ester

To the mixture of 4-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (3d) (1.74 g, 7.36 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added BBr₃ (22.0 mL, 22 mmol, 1.0 M solution in CH₂Cl₂). The reaction mixture was stirred at 0° C. for 6 hr, quenched with H₂O (100 mL), extracted with CH₂Cl₂ (2×100 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 10% EtOAc in hexanes to give a pale yellow solid (171 mg, 10% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.15 (s, 1 H) 6.99 (s, 1 H) 5.87 (s, 1 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.50 (s, 6 H); LCMS for C₁₂H₁₄O₄ m/z 223.0 (M+H)⁺.

Preparation of Intermediate: (3,5-difluoropyridin-2-yl)(3-fluoroazetidin-1-yl)methanone

To a solution of 3,5-difluoropicolinic acid (16.40 g, 103.1 mmol), 3-fluoroazetidine (8.59 g, 114 mmol) and triethylamine (27.70 ml, 199.0 mmol) in 100 mL of DMF was added HATU (45.40 g, 119.0 mmol). The mixture was stirred at room temperature for 3 hr, quenched with water, extracted with 3× EtOAc. The combined organic layer was washed with 2×H₂O, dried with Na₂SO₄, and concentrated to provide an oil that was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a yellow solid (11.49 g, 46.3% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J=2.53 Hz, 1 H) 7.31-7.46 (m, 1 H) 5.27-5.52 (m, 1 H) 4.62-4.79 (m, 1 H) 4.42-4.59 (m, 2 H) 4.22-4.38 (m, 1 H); MS for C₉H₇F₃N₂O m/z 217.00 (M+H)⁺

Preparation of Intermediate: methyl 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate

A mixture of (3,5-difluoropyridin-2-yl)(3-fluoroazetidin-1-yl)methanone (7.49 g, 34.60 mmol), methyl 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (7.69 g, 34.60 mmol) and Cs₂CO₃ (16.90 g, 52.0 mmol) in DMF was heated to 110° C. for 30 min, cooled to room temperature, quenched with H₂O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H₂O, dried over Na₂SO₄ and concentrated. The residue was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a white foam with ˜20% impurity (10.49 g, 72% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=2.27 Hz, 1 H) 7.21-7.30 (m, 2 H) 6.98-7.06 (m, 1 H) 5.26-5.49 (m, 1 H) 4.64-4.77 (m, 1 H) 4.46-4.60 (m, 1 H) 4.28-4.42 (m, 1 H) 4.07-4.23 (m, 1 H) 3.88 (s, 3 H) 2.91 (s, 2 H) 1.49 (s, 6 H); LCMS for C₂₁H₂₀F₂N₂O₅ m/z 419.20 (M+H)⁺.

Preparation of Intermediate: 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid

To a solution of methyl 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (1.520 g, 3.633 mmol), in 10 mL THF and 10 mL MeOH was added 4.25 mL of 1N aqueous NaOH. The resulting solution was stirred at room temperature for 2 hr. The solvent was removed in vacuo. Water was added, and the mixture was washed with EtOAc. The aqueous layer was acidified with 1N HCl until pH ˜1, and extracted with 3×EtOAc. The combined organic layer was dried over Na₂SO₄ and concentrated to give a white foam (1.32 g, 90% yield), which contains ˜15% impurity. LCMS for C₂₀H₁₈F₂N₂O₅m/z 405.20 (M+H)⁺.

Biochemical Assay

Full-length glucokinase (beta cell isoform) was His-tagged at N-terminus and purified by a Ni column followed by size exclusion chromatography. Glucose was obtained from Calbiochem, and other reagents were from Sigma.

All assays were performed in a Corning 96-well plate using Spectramax PLUS spectrophotometer (Molecular Devices) at room temperature. The final assay volume was 100 uL. The buffer conditions used in this assay were as follows: 50 mM HEPES, 5 mM glucose, 1 mM ATP, 2 mM MgCl₂, 0.7mM NADH, 2 mM DTT, 1 Unit/mL PK/LDH, 0.2 mM phosphoenolpyruvate, 25 mM KCl. Tested compound in DMSO solution was added to the buffer and mixed well by a plate shaker for 1 minute. The final concentration of DMSO introduced into the assay was 1%.

Glucokinase was added to the buffer mixture to initiate the reaction in the presence and absence of compound. Reaction was monitored by absorbance at 340nm due to the depletion of NADH. The initial reaction velocity was measured by the slope of a linear time course of 200-900 sec.

The percentage of activation was calculated by the following equation: % Activation=(Va/Vo−1)×100;

wherein each of Va and Vo is defined as the initial reaction velocity in the presence and absence of the tested compound, respectively.

To determine the EC₅₀ and % max activation, compounds were serially diluted in DMSO by 3 fold. The GK activities were measured as a function of compound concentrations. The data were fitted to the equation below to obtain the EC₅₀ and % max activation values: Va/Vo=1+(% max activation/100)/(1+EC₅₀/compound concentration)

The percentage activation, EC₅₀, and percentage max activation, for the compounds exemplified in the present application are tabulated below. Compounds of the invention generally have GK activating activity with an EC₅₀ of less than 10 μM, preferably less than about 1 μM, more preferably less than about 0.1 μM.

% Activation EC50 % Max Example MW at 10 uM (uM) Activation 1 424.48 101 8.7 144 2 438.5 113 5.3 152 3 452.53 145 0.348 140 4 425.46 14.6 ND ND 5 422.46 −6.3 ND ND 6 424.48 87.6 9.6 123 7 422.46 99.7 3.7 129 8 424.48 127 2.8 100 9 422.46 72.7 3.08 94.7 10 438.5 98.7 1.1 122 11 427.48 158 2 177 12 427.48 162 3 195 13 427.48 182 1.8 196 14 384.43 167 1.3 115 15 481.53 4.3 ND ND 16 441.51 213 0.506 192 17 439.49 161 0.51 165 18 468.53 105 0.95 114 19 438.5 139 0.37 156 20 442.49 230 0.314 231 21 453.52 97.9 3.9 127 22 468.53 118 0.29 117 23 452.53 46.1 1.4 70 24 459.55 121 1.49 140 25 442.49 102 1.3 116 26 428.46 197 0.4 200 27 473.57 112 1.1 112 28 485.58 123 2 158 29 456.52 284 0.25 255 30 489.57 144 4.2 183 31 406.42 135 2.1 153 32 464.49 164 0.21 177 33 464.49 170 0.0661 171 34 464.49 75.1 >10.0 ND 35 446.5 145 0.105 145 36 441.51 130 1.1 149 37 446.5 107 0.89 143 38 413.42 109 2.4 149 39 438.5 105 2 133 40 411.43 109 3.6 150 41 494.52 138 1.4 141 42 507.56 128 2.3 139 43 500.48 164 0.73 174 44 507.56 137 0.58 146 45 480.49 150 0.57 146 46 452.48 118 0.31 138 47 476.53 140 1.05 156 48 460.53 130 0.142 114 49 489.57 133 0.455 147 50 482.49 146 0.564 149 51 494.52 129 0.25 130 52 500.48 136 0.28 151 53 507.56 125 0.65 135 54 452.48 83.3 0.0807 101 55 480.49 143 0.68 129 56 478.52 107 0.0507 108 57 507.56 131 0.643 148 58 496.51 55.3 0.075 88 59 508.55 172 0.25 168 60 508.55 172 0.27 167 61 492.55 109 0.1 107 62 494.52 153 0.7 165 63 496.51 170 0.23 158 64 496.54 172 0.27 158 65 504.52 147 0.24 141 66 482.51 149 0.41 168 67 477.49 131 0.066 130 68 482.51 146 0.66 175 69 438.46 122 0.37 129 70 452.48 132 0.15 118 71 466.51 181 0.41 167 72 468.48 182 0.95 161 73 464.49 254 0.39 232 74 478.52 285 0.54 258 75 470.47 193 0.26 189 76 488.46 203 0.47 206 77 418.45 64.4 0.15 66 78 405.5 139 1.47 149 79 435.52 148 2.1 171 80 377.44 111 5.9 176 81 392.46 112 5.3 148 82 393.45 110 5.1 135 83 407.47 78.3 8.2 148 84 359.42 58.4 >10.0 ND 85 414.5 12 ND ND 86 393.45 124 4.8 159 87 406.48 73.6 8.6 136 88 473.49 38.2 ND ND 89 341.41 139 3.9 157 90 398.49 112 5.6 138 91 425.49 150 3.5 150 92 315.37 87 9.5 164 93 354.41 95.2 9.7 136 94 383.41 116 4.4 140 95 435.48 143 0.625 145 96 383.41 107 7.3 148 97 435.48 131 3.4 123 98 446.47 154 1.6 165 99 412.51 112 4.3 136 100 411.46 171 1.6 156 101 373.45 94.7 6 125 102 359.42 92.6 8.8 137 103 420.47 78.9 4.7 94 104 423.47 149 1.8 134 105 409.44 70.1 9.4 102 106 392.46 143 2.4 141 107 468.94 173 0.097 163 108 468.94 82.2 0.076 107 109 470.47 86.9 0.28 83 110 482.49 139 0.072 131 111 470.47 85.2 0.045 115 112 470.47 130 0.044 153 113 399.4 239 2.6 265 114 459.5 156 0.203 164 115 459.5 79.7 8.8 141 116 470.52 110 0.073 112 117 460.48 325 0.15 283 118 476.94 244 0.32 251 119 476.94 242 0.43 223 120 470.52 80.5 0.2 79 121 459.5 124 0.5 152 122 470.55 184 0.1 159 123 481.57 189 0.055 150 124 493.58 156 0.038 113 125 482.56 181 0.046 162 126 466.56 137 0.037 118 127 455.53 193 0.066 165 128 481.57 135 0.038 112 129 467.54 185 0.089 160 130 488.54 211 0.14 236 131 468.53 292 0.21 272 132 489.53 288 0.17 280 133 456.52 308 0.12 293 134 471.54 300 0.19 271 135 474.51 239 0.097 257 136 473.52 237 0.12 236 137 475.95 212 0.27 218 138 507.52 218 0.34 224 139 475.95 242 0.55 254 140 486.52 196 0.17 236 141 485.53 173 0.11 216 142 453.47 145 0.0528 130 143 453.47 47.8 0.179 50 144 439.44 103 0.269 100 145 479.51 47.2 0.0727 46.5 146 492.51 25.1 ND ND 147 518.59 35 ND ND 148 463.51 49.5 0.0428 53 149 434.49 105 0.12 104 150 445.52 39.1 0.11 55 151 432.48 98.1 0.47 97 152 420.47 90.7 0.85 98 153 435.48 168 0.15 161 154 435.48 36.3 4 54 155 461.52 38.4 0.09 43 156 432.48 52 0.46 49 157 431.49 69.2 0.19 71 158 421.45 115 0.47 106 159 465.48 243 0.15 260 160 447.49 298 0.13 250 161 435.48 191 0.175 143 162 435.48 105 1.6 135 163 487.52 118 0.44 137 164 436.47 112 0.25 102 165 446.5 76.8 0.038 57 166 421.46 203 0.41 212 167 447.49 148 0.0553 146 168 435.48 172 0.199 184 169 448.48 125 0.056 141 170 422.44 264 0.3 255 171 422.44 171 3.6 213 172 448.48 186 0.48 169 173 465.48 159 0.068 148 174 436.47 238 0.84 258 175 478.55 233 0.77 251 176 439.45 194 0.45 203 177 453.47 204 0.35 189 178 453.47 198 0.09 147 179 422.43 ND ND ND 180 408.41 66.5 >10.0 ND 181 389.41 171 1.1 182 182 432.44 244 0.29 237 183 406.42 237 1.9 236 184 407.4 250 3.2 251 185 449.44 248 0.104 227 186 450.43 135 0.16 234 187 431.45 178 >10.0 ND 188 432.44 198 0.62 230 189 465.9 219 0.87 245 190 459.5 83.9 7.3 138 191 464.49 91.2 1.7 119 192 459.5 249 2.1 285 193 420.49 116 8.8 237 194 421.48 146 5 263 195 385.42 98.9 >10.0 ND 196 384.43 62 >10.0 ND 197 464.49 77.6 >10.0 ND 198 442.49 51.4 >10.0 ND 199 441.51 40.3 >10.0 ND 200 443.48 113 2.9 147 201 457.51 107 2.8 137 202 466.47 121 0.36 108 203 477.49 82.6 0.81 91 204 480.49 73.9 2 94 205 468.48 90.8 0.42 94.5 206 468.48 91.3 0.27 102 207 468.48 127 0.95 142 208 462.5 83.9 0.71 98 209 462.5 87 0.38 96 210 462.5 130 0.85 143 211 450.49 83.5 1.3 90 212 450.49 111 2.6 144 213 450.49 83.1 0.89 113 214 407.47 12 ND ND 215 331.37 16.7 ND ND 216 345.4 13 ND ND 217 359.42 5.3 ND ND 218 358.44 43.1 >10.0 ND 219 370.45 8 ND ND 220 388.47 13.8 ND ND 221 391.47 8.4 ND ND 222 399.4 61.1 >10.0 ND 223 504.44 112 0.68 127 224 445.47 142 2.3 160 225 463.46 103 2.93 242 226 468.46 112 0.64 137 227 457.51 165 0.69 184 228 471.53 151 0.5 156 229 468.48 101 0.12 97 230 468.53 91.8 0.33 95 231 482.55 118 0.1 106 232 475.5 188 0.39 184 233 486.52 201 0.064 165 234 482.51 121 0.075 112 235 475.5 69.2 >10.0 ND 236 486.52 55.6 2.7 66 237 489.52 189 0.098 157 238 489.52 89.8 >10.0 ND 239 479.51 32.1 0.02 42 240 491.52 83 0.021 94 241 480.49 127 0.058 135 242 494.52 140 0.063 144 243 494.52 275 0.041 218 244 494.52 287 0.21 234 245 483.54 196 0.13 236 246 484.53 222 0.16 261 247 497.57 252 0.083 254 248 497.57 222 0.49 225 249 498.56 276 0.086 262 250 498.56 227 0.42 246 251 459.5 141 0.43 169 252 436.49 108 0.778 107 253 490.46 32.1 ND ND 254 462.52 53.3 3.4 71 255 426.45 18.8 ND ND 256 440.45 89.2 4.5 126 257 422.46 111 1.4 119 258 412.42 99.7 5.8 142 259 452.49 63.6 1 60 260 456.9 53.1 2.9 69 261 447.47 58.8 7.9 81 262 466.52 151 0.78 137 263 453.47 157 0.84 146 264 480.5 80.5 1.3 79 265 450.51 94.2 1.7 74 266 452.49 81.4 1 91 267 426.45 145 1.7 165 268 452.49 6.4 >10.0 ND 269 466.51 34.8 7 59 270 466.51 98.2 7.1 139 271 425.46 148 1.3 184 272 436.44 49.6 0.31 51 273 447.46 12.7 ND ND 274 450.51 131 2.4 121 275 439.49 211 2.6 210 276 443.5 20 ND ND 277 430.46 34.2 ND ND 278 420.43 131 0.47 123 279 447.45 84.3 0.43 105 280 467.5 130 2.4 148 281 437.47 92.7 2.1 87 282 427.44 140 >10.0 ND 283 426.45 132 >10.0 ND 284 454.46 86.1 5.5 218 285 493.54 121 0.547 118 286 482.52 178 2.6 224 287 510.53 80.3 0.562 169 288 483.5 161 1.7 188 289 509.54 73.8 7.8 133 290 505.55 12.8 ND ND 291 494.53 12.7 ND ND 292 495.51 16.7 ND ND 293 499.52 46.9 0.59 50 294 466.52 122 0.2 132 295 493.54 46.9 0.36 50 296 463.51 70 0.2 77 297 477.54 61.9 0.13 68 298 467.5 113 0.21 132 299 507.57 106 0.18 107 300 497.96 53.4 0.71 56 301 493.54 168 0.15 137 302 507.57 123 1.3 110 303 494.53 195 0.65 179 304 483.52 94.6 0.24 89 305 472.5 166 0.14 168 306 473.48 185 0.33 186 307 500.51 153 0.4 156 308 513.55 141 0.11 131 309 466.51 72.3 0.23 81 310 455.49 118 0.73 137 311 496.54 106 0.38 114 312 483.5 112 0.49 121 313 456.48 131 0.92 155 314 482.51 47.3 0.33 46 315 456.47 11.9 ND ND 316 452.49 73.7 0.41 78 317 441.46 186 1.7 228 318 508.55 91.3 >10.0 ND 319 479.55 59.7 5 90 320 516.58 39.2 2.5 41 321 472.47 100 4.3 132 322 461.44 161 6.3 235 323 465.45 78 3.7 83 324 408.46 18.2 ND ND 325 405.43 137 >10.0 ND 326 415.47 76.9 2.1 90 327 404.45 108 >10.0 ND 328 405.52 41.3 >10.0 ND 329 452.55 86.8 1.6 113 330 441.53 125 1.7 162 331 434.52 47.4 0.32 56 332 411.44 57.5 >10.0 ND 333 422.46 52.8 8.6 106 334 404.42 35 ND ND 335 415.45 26 ND ND 336 375.43 8.4 ND ND 337 436.49 42.6 3 89 338 425.46 84.5 4.3 147 339 429.47 −0.7 ND ND 340 389.45 41.2 >10.0 ND 341 422.41 59 1.7 69 342 433.44 15 ND ND 343 411.44 82.5 >10.0 ND 344 310.35 89.5 1.4 106 345 389.25 75.6 4 116 346 350.42 69.2 1.5 89 347 386.45 113 0.16 158 348 352.43 16.6 ND ND 349 393.44 −32.1 ND ND 350 452.55 11.2 ND ND 351 441.53 0.9 ND ND 352 434.52 12.3 ND ND 353 445.54 3.4 ND ND 354 405.52 3.5 ND ND 355 438.53 114 0.52 110 356 427.5 77.4 >10.0 ND 357 438.48 32.7 ND ND 358 449.5 50.4 0.33 56 359 452.55 69.9 0.19 70 360 441.53 129 0.62 142 361 463.53 4.2 ND ND 362 452.51 25.9 ND ND 363 438.53 52.3 7.65 99 364 427.5 45.8 >10.0 ND 365 449.5 4 ND ND 366 438.48 6.4 ND ND 367 423.45 47 5.8 59 368 426.45 48.2 >10.0 ND 369 437.47 66.1 3.7 66 370 430.46 14.9 0.17 3.5 371 439.51 35.5 ND ND 372 425.49 29.3 ND ND 373 296.33 −1.1 ND ND 374 436.94 17.7 ND ND 375 436.94 5.6 ND ND 376 451.5 73.1 6.4 90 377 402.45 25.6 ND ND 378 413.48 −1.85 ND ND 379 465.53 74.1 4.5 98 380 454.51 67.9 >10.0 ND 381 493.58 81 3 132 382 482.56 82 9.3 156 383 479.55 32.6 ND ND 384 468.53 33.2 ND ND 385 477.54 93.2 4.5 107 386 466.52 78.8 >10.0 ND 387 495.55 42.9 >10.0 ND 388 484.53 39.7 ND ND 389 496.59 32.9 ND ND 390 465.53 28.9 ND ND 391 507.61 45.2 >10.0 ND 392 507.56 48.6 >10.0 ND 394 463.51 32 ND ND 395 301.34 ND ND ND 396 448.48 204 0.36 212 397 465.48 213 0.083 202 398 461.52 128 0.056 114 399 460.49 212 0.61 231 400 456.45 192 0.14 177 401 512.56 131 0.29 139 402 512.56 19.9 ND ND 403 484.20 196 0.121 191 ND: no data was taken.

Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations that would fall into the scope of the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents. 

We claim:
 1. The compound of the formula

or a pharmaceutically acceptable salt thereof; wherein L¹ is —O—, —NR⁵—, or —S—; Ring A is (4-12)-membered heterocyclyl; each of R¹, R^(1a), and R⁴ are independently selected from H, halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁵, —(C═O)—O—R⁵, —O—(C═O)—R⁵, —NR⁵(C═O)—R⁷, —(C═O)—NR⁵R⁶, —NR⁵R⁶, —NR⁵OR⁶, —S(O)_(k)NR⁵R⁶, —S(O)_(j)(C₁-C₆)alkyl, —O—SO₂—R⁵, —NR⁵—S(O)_(k), —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), —(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)(C═)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, and —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(4-10-membered heterocyclyl; L² is >C═O, >C═O—O—, —O—C═O—, —O—C═O—O, —O—C═O—NR⁵—, —NR⁵—(C═O)—, —NR⁵—(C═O)—O—, —NR⁵—(C═O)—NR⁶, —(C═O)—NR⁵—, —O—, —NR⁵—, —S(O)_(j)—, —NR⁵SO₂—, —SO₂NR⁵—, —(C═O)NR⁵SO₂—, —SO₂NR⁵(C═O)—, or —CR⁵R⁶; R² is H, (C₁-C₆)alkyl, —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), or —(CR⁵R⁶)_(v)(4-12)-membered heterocyclyl; R³ is H, halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁵, —(C═O)—O—R⁵, —O—(C═O)—R⁵, —NR⁵(C═O)—R⁷, —(C═O)—NR⁵R⁶, —NR⁵R⁶, —NR⁵OR⁶, —S(O)_(k)NR⁵R⁶, —S(O)_(j)(C₁-C₆)alkyl, —O—SO₂—R⁵, —NR⁵—S(O)_(k), —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), —(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(q)(C═O)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(C₆-C₁₀)aryl, —(CR⁵R⁶)_(v)O(CR⁵R⁶)_(q)(4-10 membered heterocyclyl, —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(C₆-C₁₀)aryl, or —(CR⁵R⁶)_(q)S(O)_(j)(CR⁵R⁶)_(v)(4-10)-membered heterocyclyl; each of R⁵, R⁶ and R⁷ are independently selected from H, (C₁-C₆)alkyl, —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(p)(C₈-C₁₀)aryl, and —(CR⁸R⁹)_(p)(4-10)-membered heterocyclyl; any carbon atoms of the (C₁-C₆)alkyl, the (3-10)-membered cycloalkyl, the (C₆-C₁₀)aryl and the (4-10)-membered heterocyclyl of the foregoing R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently optionally substituted with 1 to 3 R¹¹ substituents each independently selected from halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, hydroxy, —O—R¹², (C₁-C₆)alkoxy, (C₁-C₆ )alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—R¹², —(C═O)—O—R⁸, —(C═O)—O—R¹², —O—(C═O)—R⁸, —O—(C═O)—R¹², —NR⁸(C═O)—R¹⁰, —(C═O)—NR⁸R⁹, —(C═O)—NR⁸R¹², —NR⁸R⁹, —NR⁸R¹², —NR⁸OR⁹, —NR⁸OR¹², —S(O)_(k)NR⁸R⁹, —S(O)_(k)NR⁸R¹², —S(O)_(j)(C₁-C₆)alkyl, —S(O)_(j)R¹², —O—SO₂—R⁸, —O—SO₂—R¹², —NR⁸—S(O)_(k), —NR¹²—S(O)_(k), —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(C₆-C₁₀)aryl, —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(v)O(CR⁸R⁹)_(q)(C₆-C₁₀)aryl, —(CR⁸R⁹)_(v)O(CR⁸R⁹)_(q)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(q)S(O)_(j) (CR⁸R⁹)_(v)(C₆-C₁₀)aryl, and —(CR⁸R⁹)_(q)S(O)_(j)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl; any carbon atoms of the (C₁-C₆)alkyl, the (3-10)-membered cycloalkyl, the (C₆-C₁₀)aryl and the (4-10)-membered heterocyclyl of the foregoing R¹¹ are independently optionally substituted with 1 to 3 R¹³ substituents each independently selected from halo, cyano, nitro, —CF₃, —CHF₂, —CH₂F, trifluoromethoxy, azido, (CH₂)_(v)OH, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—R¹², —(C═O)—O—R⁸, —(C═O)—O—R¹², —O—(C═O)—R⁸, —O—(C═O)—R¹², —NR⁸(C═O)—R¹⁰, —(C═O)—NR⁸R⁹, —NR⁸R⁹, and —NR⁸R¹²; any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹ and R¹² are independently optionally substituted with (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C═O)—R⁸, —(C═O)—O—R⁸, —(C═O)—NR⁸R⁹, —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl, —(CR⁸R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(C₆-C₁₀)aryl, or —(CR^(r)R⁹)_(q)(C═O)(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl; each R⁸, R⁹, and R¹⁰ are independently H or (C₁-C₆)alkyl; R¹² is —(CR⁸R⁹)_(v)(3-10)-membered cycloalkyl, —(CR⁸R⁹)_(v)(C₆-C₁₀aryl), or —(CR⁸R⁹)_(v)(4-10)-membered heterocyclyl; p, q, and v are each independently 0, 1, 2, 3, 4, or 5; w, n and j are each independently 0, 1, or 2; k is 1 or 2; and t and z are each independently 1, 2, 3, or 4; with the proviso that when Ring A is pyridin-2-yl or thiazol-2-yl; L¹ is —O—; L² is —O—; and R² is (C₁-C₆)alkyl, —(CR⁵R⁶)_(v)(3-10)-membered cycloalkyl, —(CR⁵R⁶)_(v)(C₆-C₁₀aryl), or —(CR⁵R⁶)_(v)(4-12)-membered heterocyclyl; then R² is further substituted by R¹¹ substituents each independently selected from —SO₂—(C₁-C₆)alkyl, —S(O)_(j)R¹², —S(O)_(k)NR⁸R⁹, —S(O)_(k)NR⁸R¹², —(C═O)—R¹², —(C═O)—NR⁸R⁹, or —(C═O)—NR⁸R¹².
 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein said Ring A is selected from the group consisting of oxadiazolyl, triazolyl, pyrrolyl, oxazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, pyridinylcyclohexyl, and naphthyridinyl.
 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein Ring A is pyrazinyl; R³ is (C₁-C₆)alkyl and n is
 1. 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein R¹ is H and R⁴ is (C₁-C₄)alkyl.
 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein L¹ is —O—; and L² is —O—.
 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R² is pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl and wherein R² is substituted with a —(C═O)—NR⁸R⁹ .
 7. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 